CA2270985A1 - Methods and compositions for stimulating neurite growth using compounds with affinity for fkbp12 in combination with neurotrophic factors - Google Patents
Methods and compositions for stimulating neurite growth using compounds with affinity for fkbp12 in combination with neurotrophic factors Download PDFInfo
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- CA2270985A1 CA2270985A1 CA002270985A CA2270985A CA2270985A1 CA 2270985 A1 CA2270985 A1 CA 2270985A1 CA 002270985 A CA002270985 A CA 002270985A CA 2270985 A CA2270985 A CA 2270985A CA 2270985 A1 CA2270985 A1 CA 2270985A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/185—Nerve growth factor [NGF]; Brain derived neurotrophic factor [BDNF]; Ciliary neurotrophic factor [CNTF]; Glial derived neurotrophic factor [GDNF]; Neurotrophins, e.g. NT-3
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Abstract
The present invention relates to methods and pharmaceutical compositions for stimulating the growth of neurites in nerve cells. The compositions comprise a neurotrophic amount of a compound and a neurotrophic factor, such as nerve growth factor (NGF). The methods comprise treating nerve cells with the above compositions or compositions comprising the compound without a neurotrophic factor. The methods of this invention can be used to promote repair of neuronal damage caused by disease or physical trauma.
Description
METHODS AND COMPOSITIONS FOR STIMULATING NEURITE GROWTH USING COMPOUNDS WITH
AFFINITY
FOR FKBP12 IN COMBINATION WTfH NEUROTROPHIC FACTORS
TECHNICAL FIELD OF THE INVENTION
The present invention relates to methods and pharmaceutical compositions for stimulating the growth of neurites in nerve cells. The compositions comprise a neurotrophic amount of a compound and a neurotrophic factor, such as nerve growth factor (NGF). The methods comprise treating nerve cells with the above compositions or compositions comprising the compound without a l0 neurotropic factor. The methods of this invention can be used to promote repair of neuronal damage caused by disease or physical trauma.
BACKGROUND OF THE INVENTION
Neurological diseases are associated with the death or injury of neuronal cells. The loss of dopaminergic neurons in the substantia nigra is the etiological cause for Parkinson's disease. Although the molecular mechanism of neurodegeneration in Alzheimer's disease is yet to be established, it is clear that brain inflammation, and deposition of beta-amyloid protein and other such agents may inhibit the survival of neurons and mitigate the growth of neurites used for communication between neurons. In patients suffering from brain ischemia or spinal cord injuries, extensive neuronal cell death is observed. Currently, there are no satisfactory treatments for these diseases.
ii Typical treatment of neurological diseases involves drugs capable of inhibiting neuronal cell death.
A more recent approach involves the promotion of nerve regeneration by promoting neurite outgrowth.
Neurite outgrowth, which is critical for the survival of neurons, is stimulated in vitro by nerve growth factors (NGF). For example, Glial Cell Line-Derived Neurotrophic Factor (GDNF) demonstrates neurotrophic activity both, in vivo and in vitro, and is currently being investigated for the treatment of Parkinson's disease. Insulin and Insulin-like growth factors have been shown to stimulate growth of neurites in rat pheochromocytoma PC12 cells and in cultured sympathetic and sensory neurons [Recio-Pinto et al., J.
Neurosci., 6, pp. 1211-1219 (1986)j. Insulin and Insulin-like growth factors also stimulate the regeneration of injured motor nerves in vivo and in vitro [Near et al., PNAS, pp. B9, 11716-11720 (1992); and Edbladh et al., Brain Res., 641, pp. 76-82 (1994)].
Similarly, fibroblast growth factor (FGF) stimulates neural proliferation [D. Gospodarowicz et al., Cell Differ., 19, p. 1 (1986)] and growth [M. A. Walter et al., Lymphokine Cytokine Res., 12, p. 135 (1993)].
There are, however, several disadvantages associated with the use of nerve growth factors for treating neurological diseases. They do not readily cross the blood-brain barrier. They are unstable in plasma. And they have poor drug delivery properties.
Recently, small molecules have been shown to stimulate neurite outgrowth in vivo. In individuals suffering from a neurological disease, this stimulation of neurite outgrowth protects neurons from further degeneration, and accelerates the regeneration of nerve cells. For example, estrogen has been shown to promote the growth of axons and dendrites, which are neurites sent out by nerve cells to communicate with each other in a developing or injured adult brain [(C. Dominique Toran-Allerand et al., J. Steroid Biochem. Mol. Biol., 56, pp.
169-78 (1996); and B. S. McEwen et al., Brain Res. Dev.
Brain. Res., 87, pp. 91-95 (1995)]. The progress of 1o Alzheimer's disease is slowed in women who take estrogen.
Estrogen is hypothesized to complement NGF and other neurotrophins and thereby help neurons differentiate and survive.
Tacrolimus, an immunosuppressive drug, has been demonstrated to act synergistically with NGF in stimulating neurite outgrowth in PC12 cells as well as sensory ganglia [Lyons et al., PNAS, 91, pp. 3191-3195 (1999)]. This compound has also been shown to, be neuroprotective in focal cerebral ischemia [J. Sharkey and S. P. Butcher, Nature, 371, pp.336-339 (1994)J and to increase the rate of axonal regeneration in injured sciatic nerve [Gold et al., J. Neurosci., 15, pp. 7509-16 (1995)].
Though a wide variety of neurological degenerative disorders may be treated by stimulating neurite outgrowth, there are relatively few agents known to possess these properties. Thus, there remains a great need for new pharmaceutically acceptable compounds and compositions that have the ability to stimulate neurite outgrowth in patients.
AFFINITY
FOR FKBP12 IN COMBINATION WTfH NEUROTROPHIC FACTORS
TECHNICAL FIELD OF THE INVENTION
The present invention relates to methods and pharmaceutical compositions for stimulating the growth of neurites in nerve cells. The compositions comprise a neurotrophic amount of a compound and a neurotrophic factor, such as nerve growth factor (NGF). The methods comprise treating nerve cells with the above compositions or compositions comprising the compound without a l0 neurotropic factor. The methods of this invention can be used to promote repair of neuronal damage caused by disease or physical trauma.
BACKGROUND OF THE INVENTION
Neurological diseases are associated with the death or injury of neuronal cells. The loss of dopaminergic neurons in the substantia nigra is the etiological cause for Parkinson's disease. Although the molecular mechanism of neurodegeneration in Alzheimer's disease is yet to be established, it is clear that brain inflammation, and deposition of beta-amyloid protein and other such agents may inhibit the survival of neurons and mitigate the growth of neurites used for communication between neurons. In patients suffering from brain ischemia or spinal cord injuries, extensive neuronal cell death is observed. Currently, there are no satisfactory treatments for these diseases.
ii Typical treatment of neurological diseases involves drugs capable of inhibiting neuronal cell death.
A more recent approach involves the promotion of nerve regeneration by promoting neurite outgrowth.
Neurite outgrowth, which is critical for the survival of neurons, is stimulated in vitro by nerve growth factors (NGF). For example, Glial Cell Line-Derived Neurotrophic Factor (GDNF) demonstrates neurotrophic activity both, in vivo and in vitro, and is currently being investigated for the treatment of Parkinson's disease. Insulin and Insulin-like growth factors have been shown to stimulate growth of neurites in rat pheochromocytoma PC12 cells and in cultured sympathetic and sensory neurons [Recio-Pinto et al., J.
Neurosci., 6, pp. 1211-1219 (1986)j. Insulin and Insulin-like growth factors also stimulate the regeneration of injured motor nerves in vivo and in vitro [Near et al., PNAS, pp. B9, 11716-11720 (1992); and Edbladh et al., Brain Res., 641, pp. 76-82 (1994)].
Similarly, fibroblast growth factor (FGF) stimulates neural proliferation [D. Gospodarowicz et al., Cell Differ., 19, p. 1 (1986)] and growth [M. A. Walter et al., Lymphokine Cytokine Res., 12, p. 135 (1993)].
There are, however, several disadvantages associated with the use of nerve growth factors for treating neurological diseases. They do not readily cross the blood-brain barrier. They are unstable in plasma. And they have poor drug delivery properties.
Recently, small molecules have been shown to stimulate neurite outgrowth in vivo. In individuals suffering from a neurological disease, this stimulation of neurite outgrowth protects neurons from further degeneration, and accelerates the regeneration of nerve cells. For example, estrogen has been shown to promote the growth of axons and dendrites, which are neurites sent out by nerve cells to communicate with each other in a developing or injured adult brain [(C. Dominique Toran-Allerand et al., J. Steroid Biochem. Mol. Biol., 56, pp.
169-78 (1996); and B. S. McEwen et al., Brain Res. Dev.
Brain. Res., 87, pp. 91-95 (1995)]. The progress of 1o Alzheimer's disease is slowed in women who take estrogen.
Estrogen is hypothesized to complement NGF and other neurotrophins and thereby help neurons differentiate and survive.
Tacrolimus, an immunosuppressive drug, has been demonstrated to act synergistically with NGF in stimulating neurite outgrowth in PC12 cells as well as sensory ganglia [Lyons et al., PNAS, 91, pp. 3191-3195 (1999)]. This compound has also been shown to, be neuroprotective in focal cerebral ischemia [J. Sharkey and S. P. Butcher, Nature, 371, pp.336-339 (1994)J and to increase the rate of axonal regeneration in injured sciatic nerve [Gold et al., J. Neurosci., 15, pp. 7509-16 (1995)].
Though a wide variety of neurological degenerative disorders may be treated by stimulating neurite outgrowth, there are relatively few agents known to possess these properties. Thus, there remains a great need for new pharmaceutically acceptable compounds and compositions that have the ability to stimulate neurite outgrowth in patients.
SUMMARY OF THE INVENTION
Applicants have solved the above problem by discovering that compounds previously invented by one of the co-applicants for use in reversing multi-drug resistance also surprisingly and unexpectedly possess neurotropic activity. These compounds are disclosed in United States patent 5,543,423 and co-pending United States application Serial No. 08/377,283 the disclosures of which are herein incorporated by reference.
These compounds stimulate neurite outgrowth in the presence of exogenous or endogenous NGF. The compositions disclosed herein comprise a compound from the genera described above and a neuronal growth factor.
Methods for stimulating neurite outgrowth disclosed herein employ the above compounds either alone or in combination with a neuronal growth factor. These methods are useful~in treating nerve damage caused by various neurological diseases and physical traumas and also in ex vivo nerve regeneration.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides pharmaceutical compositions which comprise three components. The first component is a compound having the formula (I):
K
A
JAN Z ~ ~D
( CH2 ) n 2y ~2 Fo rmu 1 a ( I ) and pharmaceutically acceptable derivatives thereof, wherein A is CHz oxygen, NR1;
wherein Rl, B and D are independently:
Ar, (C1-C6)-straight or branched alkyl, (C2-C6)-straight or branched alkenyl or alkynyl, (C5-C7)-cycloalkyl substituted (C1-C6)-straight or branched alkyl, (C3-C6)-straight or branched alkenyl or alkynyl, to (C5-C7)-cycloalkenyl substituted (C1-C6)-straight or branched alkyl, (C3-C6)-straight or branched alkenyl or alkynyl, Ar-substituted (C1-C6)-straight or branched alkyl, or Ar-substituted (C3-C6)-straight or branched alkenyl or alkynyl, wherein any one of the CHz groups of said alkyl chains is optionally replaced by a heteroatom selected from the group consisting of 0, S, SO, SOz. and NR, wherein R is selected from hydrogen, (C1-C4)-straight or branched alkyl, (C3-C9)-straight or branched alkenyl or alkynyl, or (C1-C4) bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said heteroatom containing chain to form a ring, and wherein said ring is optionally fused to an Ar group;
J is selected from hydrogen, (C1-C6)-straight or branched alkyl, (C3-C6)-straight or branched alkenyl, or -CHZAr;
i WO 98l20893 PCT/US97/20868 -K is selected from (C1-C4)-straight or branched alkyl, -CHzAr, or cyclohexylmethyl;
or J and K are taken together to form a 5-7 membered heterocyclic ring which optionally contains a heteroatom selected from O, S, SO or SO2;
Z is O or S;
Y is 0 or N, wherein, when Y is O, then R1 is a lone pair (as used herein, the term "lone pair" refers to a lone pair of l0 electrons, such as the lone pair of electrons present on divalent oxygen) and RZ is selected from Ar, (C1-C6)-straight or branched alkyl, or (C3-C6)-straight or branched alkenyl or alkynyl; and when Y is N, then R1 and RZ are independently selected from Ar, (C1-C6)-straight or branched alkyl, or (C3-C6)-straight or branched alkenyl or alkynyl; or R1 and RZ are taken together to form a heterocyclic 5-6 membered ring selected from pyrrolidine, imidazolidine, pyrazolidine, piperidine, or piperazine;
wherein Ar is selected from phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl, or anthracenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isotriazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, l,3,5-trithianyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl, benzo[b]thio-phenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, 1,2,3,4-tetrahydro-quinolinyl, isoquinolinyl, - 1,2,3,4-tetrahydro-isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, or phenoxazinyl;
wherein Ar optionally contains one to three substituents which are independently selected from hydrogen, halogen, hydroxyl, nitro, -S03H, trifluoromethyl, trifluoromethoxy, (C1-C6)-straight or branched alkyl, (C2-C6)-straight or branched alkenyl, 0-to [(C1-C5)-straight or branched alkyl], O-[(C3-C4)-straight or branched alkenyl], 0-benzyl, 0-phenyl, 1,2-methylenedioxy, -NR3R4, carboxyl, N-(Cl-C5-straight or branched alkyl or C3-C5-straight or branched alkenyl) carboxamides, N,N-di-(C1-C5-straight or branched alkyl or C3-C5-straight or branched alkenyl) carboxamides, morpholinyl, piperidinyl, O-Z, CHz- (CHZ) q-Z, 0- (CHZ) q-Z, (CHZ)q-Z-O-Z, or CH=CH-Z;
wherein R3 and R4 are independently selected from (C1-C6)-straight or branched alkyl, (C3-C6)-straight or branched alkenyl, hydrogen or benzyl; or wherein R3 and R4 are taken together to form a 5-6 membered or a 8-11 membered heterocyclic ring such as, for example, piperidinyl, morpholinyl or pyrrolidinyl;
wherein Z is selected from 4-methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazyl, quinolyl, 3,5-dimethylisoxazoyl, isoxazoyl, 2-methylthiazoyl, thiazoyl, 2-thienyl, 3-thienyl, or pyrimidyl;
wherein q is 0-2; and n is 0 or 1.
As used herein for R3 and R4, the term "heterocyclic" refers to a stable 5-6 membered monocycle or 8-11 membered bicyclic heterocycle which is either i saturated or unsaturated, and which may be optionally benzofused if monocyclic. Each heterocycle consists of carbon atoms and from one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
As used herein, the terms "nitrogen and sulfur heteroatoms" include any oxidized form of nitrogen and sulfur, and the quaternized form of any basic nitrogen.
The heterocyclic ring may be attached by any heteroatom of the cycle which results in the creation of a stable l0 structure. Typical examples of such heterocycles include piperidinyl, morpholinyl or pyrrolidinyl.
Preferably, at least one of B or D is independently a straight chain terminated by an aryl group, i.e., a group represented by the formula - (CHZ) r- (X) - (CHZ) s-Ar, wherein r is 1-4:
s is 0-1;
Ar is as defined above: and each X is independently selected from CH2, 0, S, SO, S02, or NR, wherein R is selected from hydrogen, (C1-C4)-straight or branched alkyl, (C3-C9)-straight or branched alkenyl or alkynyl, or (C1-C4) bridging alkyl wherein a bridge is formed between the nitrogen atom and the Ar group.
The preferred Ar groups of this invention include phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, and 1,2,3,4-tetrahydro-quinolinyl. Ar groups may contain one to three 3o substituents which are independently selected from hydrogen, hydroxyl, nitro, trifluoromethyl, (C1-C6)-straight or branched alkyl, 0-[(C1-C6)-straight WO 98l20893 PCTIUS97/208b8 or branched alkyl], halogen, S03H, or NR3R4, wherein R3 and R4 are as defined above.
The compounds of this invention include a11 ' optical and racemic isomers.
A "pharmaceutically acceptable derivative," as used herein denotes any pharmaceutically acceptable salt, ester, or salt of such ester, of a compound of this invention or any other compound which, upon administration to a patient, is capable of providing to (directly or indirectly) a compound of this invention, or a metabolite or residue thereof, characterized by the ability to promote or augment neurite outgrowth.
According to a preferred embodiment, the pharmaceutical compositions of the present invention comprise a compound having formula (II):
N I ~ ~w ~Ar 0i Y-R 1 w r Formula (II) and pharmaceutically acceptable derivatives thereof, wherein R1, RZ, Y, w, and Ar are as defined above.
According to another preferred embodiment, the pharmaceutical compositions of the present invention comprise a compound of formula (III):
WO 98I20893 PCTlUS97I20868 - -N 1 ~ 0~Ar 0"
2 r Formula (III) and pharmaceutically acceptable derivatives thereof, wherein R1, R2, Y, w, and Ar are as defined above.
According to yet another preferred embodiment, the pharmaceutical compositions of the present invention comprise a compound of formula (IV):
J~N~O w Ar Formula (IV) and pharmaceutically acceptable derivatives thereof, wherein R1, R2, Y, w, and Ar are as defined above, and J
to is hydrogen, (C1-C6)-straight or branched alkyl, or (C3-C6)-straight or branched alkenyl.
According to another preferred embodiment, the pharmaceutical compositions of the present invention comprise a compound of formula (V):
CA 02270985 1999-OS-04.
Ar JAN 1 ~ O O~Ar 0"
r Formula (V) and pharmaceutically acceptable derivatives thereof, wherein R,, R2, Y, w, and Ar are as defined above, and J
is hydrogen, (C1-C6)-straight or branched alkyl, or (C3-C6)-straight or branched alkenyl.
If pharmaceutically acceptable salts of the compounds are used, those salts are preferably derived from inorganic or organic acids and bases. Included among such acid salts are the following: acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, 3-phenyl-propionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate. Base salts include ammonium salts, alkali metal salts, such as sodium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts with organic bases, such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, i WO 98I20893 PCT/i1S97120868 lysine, and so forth. Also, the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides, such as benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby to obtained.
The compounds utilized in the compositions and methods of this invention may also be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and include those which increase biological penetration into a given biological system (e. g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
The second component in each of the pharmaceutical compositions described above is a neurotrophic factor. The term "neurotrophic factor", as used herein, refers to compounds which are capable of stimulating growth or proliferation of nervous tissue.
As used in this application, the term "neurotrophic factor" excludes the compounds described herein.
Numerous neurotrophic factors have been identified in the art and any of those factors may be utilized in the compositions of this invention. These neurotrophic factors include, but are not limited to, nerve growth factor (NGF), insulin growth factor (IGF-1) and its active truncated derivatives such as gIGF-1, acidic and basic fibroblast growth factor (aFGF and bFGF, respectively), platelet-derived growth factors (PDGF), brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factors (CNTF), glial cell line-derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3)and neurotrophin 4/5 (NT-4/5). The most preferred neurotrophic factor in the compositions of this invention is NGF.
The third component of the pharmaceutically acceptable compositions of this invention is a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers that may be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or 2o electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
Preferably, the compositions are administered orally, intraperitoneally or intravenously.
Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension.
These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as Ph. Helv or similar alcohol.
The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers which are WO 98l20893 PCTILTS97/20868 -commonly used include lactose and corn starch.
Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
Alternatively, the pharmaceutical compositions to of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.
The pharmaceutical compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs 2o readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above? or in a suitable enema formulation.
Topically-transdermal patches may also be used.
For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment 3o containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention i include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, to cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with our without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
The pharmaceutical compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
The amount of both, the compound and the 3o neurotrophic factor that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, the particular mode of administration. The two active ingredients of the pharmaceutical compositions of this invention act synergistically to stimulate neurite outgrowth.
Therefore, the amount of neurotrophic factor in such compositions will be less than that required in a monotherapy utilizing only that factor. Preferably, the compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the compound can be administered and a dosage of between 0.01 - 100 ~g/kg body weight/day of the neurotrophic can be administered to a patient receiving these compositions.
It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of 2o active ingredients will also depend upon the particular compound and neurotrophic factor in the composition.
Accarding to another embodiment, this invention provides methods for stimulating neurite outgrowth. In one aspect of this embodiment, the method is used to stimulate neurite outgrowth in a patient and is achieved by administering to the patient a pharmaceutically acceptable composition comprising any of the compounds described above and a pharmaceutically acceptable carrier. The amount of compound utilized in these methods is between about 0.01 and 100 mg/kg body weight/day.
i In another aspect of this embodiment, the method is used to stimulate nerve growth ex vivo. For this aspect, the compounds described above can be applied directly to the nerve cells in culture. This aspect of the invention is useful for ex vivo nerve regeneration.
According to an alternate embodiment, the method of stimulating neurite outgrowth comprises the additional step of treating a patient or ex vivo nerve cells in culture with a neurotrophic factor, such as to those contained in the pharmaceutical compositions of this invention described above. This embodiment includes administering the compound and the neurotrophic agent in a single dosage form or in separate, multiple dosage forms when they are to be administered to a patient. If separate dosage forms are utilized, they may be administered concurrently, consecutively or within less than about 5 hours of one another.
The methods and compositions of this invention may be used to treat nerve damage caused by a wide variety of diseases or physical traumas. These include, but are not limited to, Alzheimer's disease, Parkinson's disease, ALS, multiple sclerosis, stroke and ischemia associated with stroke, neural paropathy, other neural degenerative diseases, motor neuron diseases, sciatic crush, peripheral neuropathy, particularly neuropathy associated with diabetes, spinal cord injuries and facial nerve crush.
In order that the invention described herein may be more fully understood, the following examples are 3o set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner.
Examples General Methods Proton nuclear magnetic resonance ('H NMR) spectra were recorded at 500 MHz on a Bruker AMX 500.
Chemical shifts are reported in parts per million (8) relative to Me4Si (8 0.0). Analytical high performance to liquid chromatography was performed on either a Waters 600E or a Hewlett Packard 1050 liquid chromatograph.
Example 1 1,7-Dipyridin-3-yl-hept-1,6-diyne-9-of (1):
A mixture of 1,6-heptadiyn-4-of (25 g, 0.231 mol) , palladium(II) acetate (2. 6 g, I1.0 mmol) , copper(I)iodide t3.3 g, I1.0 mmol) and triphenylphosphine (9.1 g, 35.0 mmol) in degassed triethylamine (300 mL) was 2o treated with 3-bromopyridine (77 g, 0.49 mol). After stirring for 24 h at room temperature, the reaction was filtered through a plug of Celite and the Celite washed with ethyl acetate (EtOAc). The filtrate was concentrated to afford a dark brown oil. This material was dissolved in 2 N hydrochloric acid (HC1) and washed with EtOAc (2x). The pH of the aqueous layer was adjusted to pH>8 by addition of 3 N sodium hydroxide (NaOH) and then extracted with EtOAc (2x). The extract s were combined, washed with half-saturated aqueous sodium 3o chloride, brine, dried over magnesium sulfate (MgS04), filtered and concentrated. The residue was passed through a plug of silica gel (Si02), elution with EtOAc) to provide 33.1 g of compound 1 as a solid upon drying.
Example 2 1,7-Dipyridin-3-yl-he~tan-9-of (2):
A suspension of platinum oxide (280 mg) in absolute ethanol (1 mL) was diluted with absolute methanol (10 mL) followed by the addition of compound 1 (2.81 g, 10.73 mmol). The suspension was placed under 40 psi of hydrogen gas. After hydrogen consumption ceased, the hydrogen was replaced with nitrogen and the l0 reaction was filtered and concentrated to provide 2.87 g of compound 2 as a viscous oil.
Example 3 t5 (S)-Piperidine-1,2-dicarboxylic acid 1-tert-butyl ester2-(1-(3-pyridin-3-yl-propyl)-4-pyridin-3-yl)-butyl ester (3): To a solution of compound 2 (9.5 g, 35.18 mmol) and (S)-piperidine-1,2 dicarboxylic acid 1-tert-butyl ester (12.1 g, 52.7B mmol), and 2o N,N-dimethyl-4-aminopyridine (427 mg, 3.5 mmol) in methylene chloride (CHZC12, 50 mL) at 0°C was added 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (10.1 g, 52.78 mmoI). The reaction was warmed to room temperature and allowed to stir for 16 h.
25 The reaction was diluted with EtOAc, washed with water, 5$ aqueous sodium bicarbonate (NaHC03), brine, dried over anhydrous magnesium sulfate (MgS04) and concentrated to provide 16.67 g of compound 3 as a viscous oil.
30 Example 4 (S)-Piperidine-2-carboxylic acid 2-(1-(3-pyridin-3-yl-propyl)-4-pyridin-3-yl)-butyl ester (4):
To a solution of compound 3 (16.67 g, 35 34.66 mmol) in CHzCl2 (40 mL) at 0°C was added trifluoroacetic acid (40 mL). After the addition was WO 98/20893 PCT/US97l20868 -complete, the reaction was warmed to room temperature and stirred for 4 h. The reaction was concentrated and the residue taken up into water and made basic with solid KZC03. The product was extracted with CHZCIz (2x) . The extracts were combined dried over MgS04, filtered and concentrated to provide 13.20 g of compound 4 as a viscous oil.
l0 Example 5 (S)-1-((3,4,5-Trimethoxyphenyl)-methyl-carbamoyl)-piperid ine-2-carboxylic acid 4-pyridin-3-yl-1-(3-pyridin--3-yl-propyl)-butyl ester (5):
To a mixture of N-methyl-3,4,S-trimethoxy-aniline (130 mg, 0.66 mmol) and diisoproylethylamine (i-Pr2NEt, 215 ~L, 1.2 mmol) in methylene chloride (CHZC12, 1 mL) was added 1.2 M phosgene in toluene (1.65 mL). After stirring for 2 h, the reaction was concentrated and placed under vacuum to remove residual phosgene. To a solution of compound 4 (225 mg, 0 . 59 mmol ) in CHZC12 ( 1 . 5 mL) containing i-Pr2EtN ( 215 ~,L, 1.2 mmol) was added the above preformed acyl chloride in CHZC12 (1.5 mL). After stirring for 1 h, the reaction was diluted with ethyl acetate (EtOAc), washed with 5~ aq.
NaHC03, brine, dried over MgS04, filtered and concentrated in vacuo to provide a viscous oil. Chromatography of the residue on Si02 (elution with 30 to 60~ acetone:hexanes) provided 238 mg (67~) of compound 5 as a viscous oil.
1H NMR (500 MHz, CDCL3) a 8.44-8.40 (m, 4H), 7.35 (m. 2H), 7.22-7.18 (m, 2H), 6.43 (br s, 2H), 4.98 (m, 1H), 4.74 (m, 1H) ( 3.84 (s, 9H1 , 3.42 (br s, 1H) ( 3. 18 (s, 3H) , 2.92 (m, 1H), 2.6S-2.56 (m, 5H), 2.06-1.98 (m, 1H), 1.70-153 (m, 15H).
Example 6 (S)-1-((3-Trifluoromethylphenyl)-methyl-carbamoyl)-piperi dine-2-carboxylic acid 4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)-butyl ester (6):
Compound 6 was prepared according to the protocol of Example 5, except that N-methyl-3,4,5-trimethoxyaniline was replaced with N-methyl-3-trifluoro-methylaniline.
1NMR (500 MHz, CDC13) 8 8.42-8.39 (m, 4H) , 7.50-6. 16 (m, 10H), 4.99 (m, 1H), 4.64 (m, 1H), 3.29 (m, 1H), 3.20 (s, 3H), 2.93 (m, 1H), 2.67-2.53 (m, 4H), 2.03-1.99 (m, 1H), 1.69-1.53 (m, 13H).
Example 7 (S)-1-((4-Tert-butylphenyl)-methyl-carbamoyl)-piperidine-2-carboxylic acid 4-pyridin-3-yl-1-(3-pyridin-3-yl--propyl)-butyl ester (7):
Compound 7 was prepared according to the protocol of Example 5, except that N-methyl-3,4,5-trimethoxyaniline was replaced with N-methyl-4-tert-butylaniline.
1NMR (500 MHz, CDC13) 8 8.40 (m, 4H), 7.49-7.42 (m, 2H), 7.30 (d, 2H), 7.17 (m. 2H), 7.05 (d, 2H), 4.99 (m, 1H), 4. 64 (m, 1H) , 3. 35 (m, 1H) , 3.14 (s, 3H) , 2 . 84 (dt, 1H) , 2.64-2.52 m, 4H), 2.00-1.95 (m, 1H), 1.70-1.48 (m, 11H), 1.27 (s, 9H) , 1.20-1 .02 (m, 2H) .
Example 8 (S)-1-((4-Isopropylphenyl)-methyl-carbamoyl)-piperidine-2 -carboxylic acid 4-pyridin-3-yl-1-(3-pyridin--3-yl-propyl)-butyl ester (8):
Compound 8 was prepared according to the protocol of Example 5, except that N-WO 98l20893 PCT/US97/20868 --methyl-3,4,5-trimethoxyaniline was replaced with N-methyl-4-iso-propylaniline.
1H NMR (500 MHz, CDC13) a 8.42-8.39 (m, 4H), 7.99-7.43 (m, 2H), 7.18 (m, 2H), 7.14 (d. 2H), 7.06 (d, 2H), 4.99 (m, 1H) , 4 . 64 (m, 1H) , 3. 35 (br d, 1H) , 3. 15 (s, 3H) , 2 . 85 (m, 2H), 2.59 (m, 9H), 1.97 (m, 1H), 1.70-l.99 (m, 11H), l.21 (d, 6H), 1.20-1.02 (m, 2H).
l0 Example 9 (S)-1-{Piperidine-1-carbonyl)-piperidine-2-carboxylic acid 4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)-butyl ester (9) Compound 9 was prepared according to the protocol of Example 5, except that N-methyl-3,4,5-trimethoxyaniline was replaced with N-piperidine.
1H NMR (50D MHz, CDCls) 8 8.42-8.39 (m, 4H) , 7.50-7. 43 (m, 2H), 7.24-7.16 (m, 2H), 4.98 (m, 1H), 4.67 (t, 1H), 3.32-3.09 {m, 8H), 2.64-2.52 (m, 6H), 2.01-1.96 (m, 1H), 1.80-1.30 (m, 15H).
Example 10 (S)-1-{(3,4,5-Trimethoxyphenyl)-methyl-carbamoyl)-piperid ine-2-carboxylic acid 4-pyridin-1-yl-1-(3-pyridin--1-yl-~ropyl ) -butyl ester ( 10 ) Compound 10 was prepared according to the protocols of Examples 1-5, except that 3-bromopyridine 3o was replaced with 1-bromopyridine.
1H NMR {500 MHz, CDC13) 8 8.50 (t, 2H), 7.56 (dq, 2H), 7.18-7.08 (m, 4H), 6.43 {s, 2H), 4.97 (q, 1H), 4.78 (m, 1H) , 3.83 (s, 9H) , 3.44 (br d, 1H) , 3.19 (s, 3H) ( 2. 89 (dt, iH), 2.82-2.73 (m, 4H), 2.07 (br d, 1H), 1.81-1.52 (m, 12H) .
i Example 11 (S)-Piperidine-1,2-dicarboxyiic acid 1-(3,4,5-trimethoxyphenyl) ester 2-(4-pyridin-3-yl-1--(3-pyridin-3-yl-propyl)-butyl) ester (11):
Compound 11 was prepared according to the protocol of Example 5, except that N-methyl-3,4,5-trimethoxyaniline was replaced with 3,4,5-trimethoxyphenol. Compound 11 was obtained as a to mixture of rotomers:
1H NMR (500 MHz, CDC13) a 8.42-8.35 (m), 7.50-7.32 (m), 7.28-7.18 (m), 6.39 (s), 6.27 (s), 5.34-4.90 (m), 4.19-4.01(m), 3.78 (s), 3.75 (s), 3.22 (br dt), 3.14 (quintet), 3.05-2.90 (m), 2.65-2.53 (m), 2.27-2.21 (m), 15. 2. 02 (s) , 1 . 80-1 .95 (m) .
Example 12 (S)-Piperidine-2-carboxylic acid 2-(1-(2-phenyl--20 ethyl)-3-phenyl-propyl ester (12):
Compound I2 was prepared according to the protocols of Examples 3-4, except that compound 2 in Example 3 was replaced with 1,5-diphenylpentan-3-ol.
25 Example 13 (S)-1-((3,4,5-Trimethoxyphenyl)-methyl-carbamoyl)-piperid ine-2-carboxylic acid 1-(2-phenyl-ethyl)-3-phenyl-propyl ester (13):
30 Compound 13 was prepared according to the protocol of Example 5, except that compound 4 was replaced with compound _12.
1H NMR (500 MHz, CDC13) a 7.27 (m, 4H) , 7.20-7.14 (m, 6H) , 6.47 (s, 2H), 5.01 (m, 1H), 4.87 (m, 1H), 3.84 (s, 6H), 35 3. 83 (s, 3H) , 3. 48 (br d, 1H) , 3.23 (s, 3H) , 2 . 94 (dt, 1H), 2.72-2.94 (m, 4H), 2.17-2.10 (m, 1H), 2.00-1.85 (m, CA 02270985 1999-OS-04 .
4H), 1.67-1.60 (m, 2H), 1.45-1.40 (m, 1H), I.30-Z.18 (m, 2H) .
Example 14 4-(Methyl-(2-(1-phenethyl-3-phenyl-propoxycarbonyl)-piper idine-1-carbonyl)-amino)-benzenesulfonic acid (14):
Compound 14 was prepared according to the protocol of Example 13, except that N-methyl-3,4,5-trimethoxyaniline to was replaced with N-methyl-9-aminophenyl sulfonic acid.
Example 15 (S)-Piperidine-2-carboxylic acid 1-benzvloxvmethvl-2--benzyloxyethyl ester (15):
Compound 15 was prepared according to the protocols of Examples 3-4, except that compound 2 in Example 3 was replaced with 1,3-dibenzyloxypropan-2-ol.
Example 16 (S)-1-(Methyl-(9-morpholin-1-yl phenyl)-carbamoyl)-piperi dine-2-carbox~rlic acid 2-benzyloxy-1-(benzyloxy--methyl)-ethyl ester (16):
Compound 16 was prepared according to the protocol of Example 5, except that compound 4 was replaced with compound 15 and N-methyl-3,4,5-trimethoxy-aniline with N-methyl-4-morpholinoaniline.
1H NMR (500 MHz, CDC13) 8 7.34-7.11 (m, 10H), 7.09 (d, 2H) , 6. 84 (d, 2H) , 5.29 (quintet, 1H) , 4 . 81 (br t, IH) , 4. 54 (d, 2H) , 4.99 (dd, 2H) , 3.84 (t, 2H) , 3. 67 (t, 2H) , 3.40 (br d, 1H), 3.15 (s, 3H), 3.09 (t, 4H), 2.86 (dt, 1H), 2.08-2.05 (m, 1H), 1.60-1.44 (m, 2H), 1.27-1.08 (m, 3H) .
i WO 98l20893 PCTlUS97I20868 -Example 17 (S)-1-(Methyl-(4-piperidin-1-yi-phenyl)-carbamoyl)-piperi dine-2-carboxylic acid 2-benzyloxy-1-(benzyloxy --methyl)-ethyl ester (17):
Compound 17 was prepared according to the protocol of Example 16, except that N-methyl-3,4,5-trimethoxyaniline was replaced with N-methyl-4-piperdinoaniline.
'H NMR (500 MHz, CDC13) E 7.36-7.25 (m, 10H) ( 7.06 (d, 2H), 6.86 (d, 2H), 5.29 (quintet, 1H), 4.79 (m, 1H), 4 . 55-4 . 48 (m, 4H) , 3. 66 (m, 4H) , 3.41 (br d, 1H) , 3. 14 (s, 3H), 3.10 (m, 4H), 2.87 (dt, 1H), 2.05 (br d, 1H), 1.73-1.67 (m, 4H), 1.61-1.45 (m, 4H), 1.25-1.08 (m, 3H).
Example 18 (S)-Piperidine-1,2-dicarboxylic acid 2-(2-benzyloxy-1-(benzyloxymethyl)-ethyl)ester 1-quinolin-5-yl ester (I8):
Compound 18 was prepared according to the protocol of Example 16, except that N-methyl-3,4,5--trimethoxyaniline was replaced with 5-hydroxyquinoline.
Compound _18 was a mixture of rotomers.
'H NMR (500 MHz, CDC13) 8 8.89 (dd) , 8.86 (dd) , 8. 90 (d) , 8.24 (d), 7.89 (t), 7.67 (t), 7.63 (t), 7.36-7.18 (m), 5. 44 (quintet) , 5.36 (quintet) , 5.20 (d) , 5. 02 (d) , 4.56-4.94 (m), 4.34 (br d), 4.14 (br d), 3.72-3.56 (m), 3.39 (dt), 3.09 (dt), 2.38 (br t), 1.90-i.49 (m), 1.40-1.29 (m).
Example 19 (S)-Piperidine-1,2-dicarboxylic acid 2-(2-benzyloxy 1-(benzyloxymethyl)-ethyl)ester 1-pyridin-3-yl ester (I9) .........._ .".."..~.-..»~.-.....---,.~T.....~........ ... ........._ -"........".... ....
Compound 19 was prepared according to the protocol of Example 16, except that N-methyl-3,4,5-trimethoxyaniline was replaced with 3-hydroxypyridine. Compound 19 was a mixture of rotomers.
1H NMR (500 MHz, CDC13) a 8.46-8.41 (m), 7.48 (dt), 7.43 (dt) , 7 . 34-7.24 (m) , 7 . 18 (dd) , 5. 40-5. 33 (m) , 5. 03 (dd) 4.57-9.47 (m), 4.17 (br d), 3.69-3.66 (m), 3.27 (dt), 3.05 (dt), 2.33 (br d), 1.81-1.71(m), 1.&9-1.64 (m), l0 1 . 56-1 . 43 (m) , 1 . 35-1 .27 (m) .
Example 20 2-(1,3-Dimethyl-3(3,4,5-trimethoxyphenyl)ureido)-3 phenyl-propanoic acid 4-pyridin-3-yl-1-(3-pyridin--3-yl-propyl)-butyl ester(20):
Compound 20 is prepared according to the protocols of Examples 3-5, by replacing (S)-piperidine-1,2- -dicarboxylic acid 1-tert-butyl ester 2o with N-(tert-butoxycarbonyl)-L-phenylalanine.
Example 21 2-(1,3-Dimethyl-3-(3,4,5-trimethoxyphenyl)ureido)-3-(phen yl)-pro~anoic acid 3-pyridin-3-yl-1-(2-pyridin-3-yl-ethyl)-propyl ester (21l:
Compound 21 is prepared according to the protocols of Examples 3-5, by replacing (S)-piperidine--1,2-dicarboxylic acid 1-tert-butyl ester with 3o N-(tert-butoxycarbonyl)-L-phenylalanine and 1,7-dipyridin-3-yl-heptan-9-oI with 1,5-dipyridin --3-yl-pentan-3-ol.
WO 98I20893 PCTIUS971208b8 -Example 22 N-Methyl-2-phenylethylamine-1,2-dicarboxvlic acid 1-(3,4,5-trimethoxyphenyl) ester 2-(4-pyridin-3-yl -I-(3-pyridin-3-yl-propyl)butyl) ester (22):
Compound 22 is prepared according to the protocol of Example 20, by replacing N-methyl-3,4,5-trimethoxyaniline with 3,4,5-trimethoxyphenol.
Example 23 N-Methyl-2-phenylethylamine-1,2-dicarboxylic acid 1-(3,4,5-trimethoxyphenyl) ester 2-(3-pyridin-3-yl--1-(2-pyridin-3-yl-ethyl)propyl) ester (23):
Compound 23 is prepared according to the protocol of Example 21, by replacing N-methyl-3,4,5-trimethoxyaniline with 3,4,5-trimethoxy-phenol.
Example 24 In order to directly determine the neurotrophic activity of compounds described in this invention, the neurite outgrowth assay was carried out with pheochromocytoma PC12 cells as described by Lyons et al . ( 1994 ) .
PC12 cells are mainatined at 37 degree and 5~
C02 in Dulbecco's modified Eagle's medium (DMEM) suppplemented with 10~ heat-inactivated horse serum, 5$
heat-inactivated fetal bovine serum (FBS), and 1~
3o glutamate. The cells are then plated at 105 per well in 96 well plates coated with 5 ~/cm2 rat tail collagen and allowed to attach overnight. The medium is then replced with DMEM, 2$ heat-inactivated horse serum, 1~
WO 98l20893 PCTIUS97120868 -glutamate, 1-5 ng/ml of NGF (Sigma) and varying concentrations of compound (0.1 nM- 10 nM). The background control culture is administered with 105 ng/ml of NGF alone without compound. Positive control cultures are administered with high concentration of NGF (50 nglml ) .
The compounds described in this invention herein cause a significant increase in neurite outgrowth over background control cultures.
to While we have hereinbefore presented a number of embodiments of this invention, it is apparent that my basic construction can be altered to provide other embodiments which utilize the methods of this invention.
Therefore, it will be appreciated that the scope of this invention is to be defined by the claims appended hereto rather than the specific embodiments which have been presented hereinbefore by way of example.
Applicants have solved the above problem by discovering that compounds previously invented by one of the co-applicants for use in reversing multi-drug resistance also surprisingly and unexpectedly possess neurotropic activity. These compounds are disclosed in United States patent 5,543,423 and co-pending United States application Serial No. 08/377,283 the disclosures of which are herein incorporated by reference.
These compounds stimulate neurite outgrowth in the presence of exogenous or endogenous NGF. The compositions disclosed herein comprise a compound from the genera described above and a neuronal growth factor.
Methods for stimulating neurite outgrowth disclosed herein employ the above compounds either alone or in combination with a neuronal growth factor. These methods are useful~in treating nerve damage caused by various neurological diseases and physical traumas and also in ex vivo nerve regeneration.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides pharmaceutical compositions which comprise three components. The first component is a compound having the formula (I):
K
A
JAN Z ~ ~D
( CH2 ) n 2y ~2 Fo rmu 1 a ( I ) and pharmaceutically acceptable derivatives thereof, wherein A is CHz oxygen, NR1;
wherein Rl, B and D are independently:
Ar, (C1-C6)-straight or branched alkyl, (C2-C6)-straight or branched alkenyl or alkynyl, (C5-C7)-cycloalkyl substituted (C1-C6)-straight or branched alkyl, (C3-C6)-straight or branched alkenyl or alkynyl, to (C5-C7)-cycloalkenyl substituted (C1-C6)-straight or branched alkyl, (C3-C6)-straight or branched alkenyl or alkynyl, Ar-substituted (C1-C6)-straight or branched alkyl, or Ar-substituted (C3-C6)-straight or branched alkenyl or alkynyl, wherein any one of the CHz groups of said alkyl chains is optionally replaced by a heteroatom selected from the group consisting of 0, S, SO, SOz. and NR, wherein R is selected from hydrogen, (C1-C4)-straight or branched alkyl, (C3-C9)-straight or branched alkenyl or alkynyl, or (C1-C4) bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said heteroatom containing chain to form a ring, and wherein said ring is optionally fused to an Ar group;
J is selected from hydrogen, (C1-C6)-straight or branched alkyl, (C3-C6)-straight or branched alkenyl, or -CHZAr;
i WO 98l20893 PCT/US97/20868 -K is selected from (C1-C4)-straight or branched alkyl, -CHzAr, or cyclohexylmethyl;
or J and K are taken together to form a 5-7 membered heterocyclic ring which optionally contains a heteroatom selected from O, S, SO or SO2;
Z is O or S;
Y is 0 or N, wherein, when Y is O, then R1 is a lone pair (as used herein, the term "lone pair" refers to a lone pair of l0 electrons, such as the lone pair of electrons present on divalent oxygen) and RZ is selected from Ar, (C1-C6)-straight or branched alkyl, or (C3-C6)-straight or branched alkenyl or alkynyl; and when Y is N, then R1 and RZ are independently selected from Ar, (C1-C6)-straight or branched alkyl, or (C3-C6)-straight or branched alkenyl or alkynyl; or R1 and RZ are taken together to form a heterocyclic 5-6 membered ring selected from pyrrolidine, imidazolidine, pyrazolidine, piperidine, or piperazine;
wherein Ar is selected from phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl, or anthracenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isotriazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, l,3,5-trithianyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl, benzo[b]thio-phenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, 1,2,3,4-tetrahydro-quinolinyl, isoquinolinyl, - 1,2,3,4-tetrahydro-isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, or phenoxazinyl;
wherein Ar optionally contains one to three substituents which are independently selected from hydrogen, halogen, hydroxyl, nitro, -S03H, trifluoromethyl, trifluoromethoxy, (C1-C6)-straight or branched alkyl, (C2-C6)-straight or branched alkenyl, 0-to [(C1-C5)-straight or branched alkyl], O-[(C3-C4)-straight or branched alkenyl], 0-benzyl, 0-phenyl, 1,2-methylenedioxy, -NR3R4, carboxyl, N-(Cl-C5-straight or branched alkyl or C3-C5-straight or branched alkenyl) carboxamides, N,N-di-(C1-C5-straight or branched alkyl or C3-C5-straight or branched alkenyl) carboxamides, morpholinyl, piperidinyl, O-Z, CHz- (CHZ) q-Z, 0- (CHZ) q-Z, (CHZ)q-Z-O-Z, or CH=CH-Z;
wherein R3 and R4 are independently selected from (C1-C6)-straight or branched alkyl, (C3-C6)-straight or branched alkenyl, hydrogen or benzyl; or wherein R3 and R4 are taken together to form a 5-6 membered or a 8-11 membered heterocyclic ring such as, for example, piperidinyl, morpholinyl or pyrrolidinyl;
wherein Z is selected from 4-methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazyl, quinolyl, 3,5-dimethylisoxazoyl, isoxazoyl, 2-methylthiazoyl, thiazoyl, 2-thienyl, 3-thienyl, or pyrimidyl;
wherein q is 0-2; and n is 0 or 1.
As used herein for R3 and R4, the term "heterocyclic" refers to a stable 5-6 membered monocycle or 8-11 membered bicyclic heterocycle which is either i saturated or unsaturated, and which may be optionally benzofused if monocyclic. Each heterocycle consists of carbon atoms and from one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
As used herein, the terms "nitrogen and sulfur heteroatoms" include any oxidized form of nitrogen and sulfur, and the quaternized form of any basic nitrogen.
The heterocyclic ring may be attached by any heteroatom of the cycle which results in the creation of a stable l0 structure. Typical examples of such heterocycles include piperidinyl, morpholinyl or pyrrolidinyl.
Preferably, at least one of B or D is independently a straight chain terminated by an aryl group, i.e., a group represented by the formula - (CHZ) r- (X) - (CHZ) s-Ar, wherein r is 1-4:
s is 0-1;
Ar is as defined above: and each X is independently selected from CH2, 0, S, SO, S02, or NR, wherein R is selected from hydrogen, (C1-C4)-straight or branched alkyl, (C3-C9)-straight or branched alkenyl or alkynyl, or (C1-C4) bridging alkyl wherein a bridge is formed between the nitrogen atom and the Ar group.
The preferred Ar groups of this invention include phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, and 1,2,3,4-tetrahydro-quinolinyl. Ar groups may contain one to three 3o substituents which are independently selected from hydrogen, hydroxyl, nitro, trifluoromethyl, (C1-C6)-straight or branched alkyl, 0-[(C1-C6)-straight WO 98l20893 PCTIUS97/208b8 or branched alkyl], halogen, S03H, or NR3R4, wherein R3 and R4 are as defined above.
The compounds of this invention include a11 ' optical and racemic isomers.
A "pharmaceutically acceptable derivative," as used herein denotes any pharmaceutically acceptable salt, ester, or salt of such ester, of a compound of this invention or any other compound which, upon administration to a patient, is capable of providing to (directly or indirectly) a compound of this invention, or a metabolite or residue thereof, characterized by the ability to promote or augment neurite outgrowth.
According to a preferred embodiment, the pharmaceutical compositions of the present invention comprise a compound having formula (II):
N I ~ ~w ~Ar 0i Y-R 1 w r Formula (II) and pharmaceutically acceptable derivatives thereof, wherein R1, RZ, Y, w, and Ar are as defined above.
According to another preferred embodiment, the pharmaceutical compositions of the present invention comprise a compound of formula (III):
WO 98I20893 PCTlUS97I20868 - -N 1 ~ 0~Ar 0"
2 r Formula (III) and pharmaceutically acceptable derivatives thereof, wherein R1, R2, Y, w, and Ar are as defined above.
According to yet another preferred embodiment, the pharmaceutical compositions of the present invention comprise a compound of formula (IV):
J~N~O w Ar Formula (IV) and pharmaceutically acceptable derivatives thereof, wherein R1, R2, Y, w, and Ar are as defined above, and J
to is hydrogen, (C1-C6)-straight or branched alkyl, or (C3-C6)-straight or branched alkenyl.
According to another preferred embodiment, the pharmaceutical compositions of the present invention comprise a compound of formula (V):
CA 02270985 1999-OS-04.
Ar JAN 1 ~ O O~Ar 0"
r Formula (V) and pharmaceutically acceptable derivatives thereof, wherein R,, R2, Y, w, and Ar are as defined above, and J
is hydrogen, (C1-C6)-straight or branched alkyl, or (C3-C6)-straight or branched alkenyl.
If pharmaceutically acceptable salts of the compounds are used, those salts are preferably derived from inorganic or organic acids and bases. Included among such acid salts are the following: acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, 3-phenyl-propionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate. Base salts include ammonium salts, alkali metal salts, such as sodium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts with organic bases, such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, i WO 98I20893 PCT/i1S97120868 lysine, and so forth. Also, the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides, such as benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby to obtained.
The compounds utilized in the compositions and methods of this invention may also be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and include those which increase biological penetration into a given biological system (e. g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
The second component in each of the pharmaceutical compositions described above is a neurotrophic factor. The term "neurotrophic factor", as used herein, refers to compounds which are capable of stimulating growth or proliferation of nervous tissue.
As used in this application, the term "neurotrophic factor" excludes the compounds described herein.
Numerous neurotrophic factors have been identified in the art and any of those factors may be utilized in the compositions of this invention. These neurotrophic factors include, but are not limited to, nerve growth factor (NGF), insulin growth factor (IGF-1) and its active truncated derivatives such as gIGF-1, acidic and basic fibroblast growth factor (aFGF and bFGF, respectively), platelet-derived growth factors (PDGF), brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factors (CNTF), glial cell line-derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3)and neurotrophin 4/5 (NT-4/5). The most preferred neurotrophic factor in the compositions of this invention is NGF.
The third component of the pharmaceutically acceptable compositions of this invention is a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers that may be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or 2o electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
Preferably, the compositions are administered orally, intraperitoneally or intravenously.
Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension.
These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as Ph. Helv or similar alcohol.
The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers which are WO 98l20893 PCTILTS97/20868 -commonly used include lactose and corn starch.
Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
Alternatively, the pharmaceutical compositions to of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.
The pharmaceutical compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs 2o readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above? or in a suitable enema formulation.
Topically-transdermal patches may also be used.
For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment 3o containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention i include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, to cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with our without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
The pharmaceutical compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
The amount of both, the compound and the 3o neurotrophic factor that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, the particular mode of administration. The two active ingredients of the pharmaceutical compositions of this invention act synergistically to stimulate neurite outgrowth.
Therefore, the amount of neurotrophic factor in such compositions will be less than that required in a monotherapy utilizing only that factor. Preferably, the compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the compound can be administered and a dosage of between 0.01 - 100 ~g/kg body weight/day of the neurotrophic can be administered to a patient receiving these compositions.
It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of 2o active ingredients will also depend upon the particular compound and neurotrophic factor in the composition.
Accarding to another embodiment, this invention provides methods for stimulating neurite outgrowth. In one aspect of this embodiment, the method is used to stimulate neurite outgrowth in a patient and is achieved by administering to the patient a pharmaceutically acceptable composition comprising any of the compounds described above and a pharmaceutically acceptable carrier. The amount of compound utilized in these methods is between about 0.01 and 100 mg/kg body weight/day.
i In another aspect of this embodiment, the method is used to stimulate nerve growth ex vivo. For this aspect, the compounds described above can be applied directly to the nerve cells in culture. This aspect of the invention is useful for ex vivo nerve regeneration.
According to an alternate embodiment, the method of stimulating neurite outgrowth comprises the additional step of treating a patient or ex vivo nerve cells in culture with a neurotrophic factor, such as to those contained in the pharmaceutical compositions of this invention described above. This embodiment includes administering the compound and the neurotrophic agent in a single dosage form or in separate, multiple dosage forms when they are to be administered to a patient. If separate dosage forms are utilized, they may be administered concurrently, consecutively or within less than about 5 hours of one another.
The methods and compositions of this invention may be used to treat nerve damage caused by a wide variety of diseases or physical traumas. These include, but are not limited to, Alzheimer's disease, Parkinson's disease, ALS, multiple sclerosis, stroke and ischemia associated with stroke, neural paropathy, other neural degenerative diseases, motor neuron diseases, sciatic crush, peripheral neuropathy, particularly neuropathy associated with diabetes, spinal cord injuries and facial nerve crush.
In order that the invention described herein may be more fully understood, the following examples are 3o set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner.
Examples General Methods Proton nuclear magnetic resonance ('H NMR) spectra were recorded at 500 MHz on a Bruker AMX 500.
Chemical shifts are reported in parts per million (8) relative to Me4Si (8 0.0). Analytical high performance to liquid chromatography was performed on either a Waters 600E or a Hewlett Packard 1050 liquid chromatograph.
Example 1 1,7-Dipyridin-3-yl-hept-1,6-diyne-9-of (1):
A mixture of 1,6-heptadiyn-4-of (25 g, 0.231 mol) , palladium(II) acetate (2. 6 g, I1.0 mmol) , copper(I)iodide t3.3 g, I1.0 mmol) and triphenylphosphine (9.1 g, 35.0 mmol) in degassed triethylamine (300 mL) was 2o treated with 3-bromopyridine (77 g, 0.49 mol). After stirring for 24 h at room temperature, the reaction was filtered through a plug of Celite and the Celite washed with ethyl acetate (EtOAc). The filtrate was concentrated to afford a dark brown oil. This material was dissolved in 2 N hydrochloric acid (HC1) and washed with EtOAc (2x). The pH of the aqueous layer was adjusted to pH>8 by addition of 3 N sodium hydroxide (NaOH) and then extracted with EtOAc (2x). The extract s were combined, washed with half-saturated aqueous sodium 3o chloride, brine, dried over magnesium sulfate (MgS04), filtered and concentrated. The residue was passed through a plug of silica gel (Si02), elution with EtOAc) to provide 33.1 g of compound 1 as a solid upon drying.
Example 2 1,7-Dipyridin-3-yl-he~tan-9-of (2):
A suspension of platinum oxide (280 mg) in absolute ethanol (1 mL) was diluted with absolute methanol (10 mL) followed by the addition of compound 1 (2.81 g, 10.73 mmol). The suspension was placed under 40 psi of hydrogen gas. After hydrogen consumption ceased, the hydrogen was replaced with nitrogen and the l0 reaction was filtered and concentrated to provide 2.87 g of compound 2 as a viscous oil.
Example 3 t5 (S)-Piperidine-1,2-dicarboxylic acid 1-tert-butyl ester2-(1-(3-pyridin-3-yl-propyl)-4-pyridin-3-yl)-butyl ester (3): To a solution of compound 2 (9.5 g, 35.18 mmol) and (S)-piperidine-1,2 dicarboxylic acid 1-tert-butyl ester (12.1 g, 52.7B mmol), and 2o N,N-dimethyl-4-aminopyridine (427 mg, 3.5 mmol) in methylene chloride (CHZC12, 50 mL) at 0°C was added 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (10.1 g, 52.78 mmoI). The reaction was warmed to room temperature and allowed to stir for 16 h.
25 The reaction was diluted with EtOAc, washed with water, 5$ aqueous sodium bicarbonate (NaHC03), brine, dried over anhydrous magnesium sulfate (MgS04) and concentrated to provide 16.67 g of compound 3 as a viscous oil.
30 Example 4 (S)-Piperidine-2-carboxylic acid 2-(1-(3-pyridin-3-yl-propyl)-4-pyridin-3-yl)-butyl ester (4):
To a solution of compound 3 (16.67 g, 35 34.66 mmol) in CHzCl2 (40 mL) at 0°C was added trifluoroacetic acid (40 mL). After the addition was WO 98/20893 PCT/US97l20868 -complete, the reaction was warmed to room temperature and stirred for 4 h. The reaction was concentrated and the residue taken up into water and made basic with solid KZC03. The product was extracted with CHZCIz (2x) . The extracts were combined dried over MgS04, filtered and concentrated to provide 13.20 g of compound 4 as a viscous oil.
l0 Example 5 (S)-1-((3,4,5-Trimethoxyphenyl)-methyl-carbamoyl)-piperid ine-2-carboxylic acid 4-pyridin-3-yl-1-(3-pyridin--3-yl-propyl)-butyl ester (5):
To a mixture of N-methyl-3,4,S-trimethoxy-aniline (130 mg, 0.66 mmol) and diisoproylethylamine (i-Pr2NEt, 215 ~L, 1.2 mmol) in methylene chloride (CHZC12, 1 mL) was added 1.2 M phosgene in toluene (1.65 mL). After stirring for 2 h, the reaction was concentrated and placed under vacuum to remove residual phosgene. To a solution of compound 4 (225 mg, 0 . 59 mmol ) in CHZC12 ( 1 . 5 mL) containing i-Pr2EtN ( 215 ~,L, 1.2 mmol) was added the above preformed acyl chloride in CHZC12 (1.5 mL). After stirring for 1 h, the reaction was diluted with ethyl acetate (EtOAc), washed with 5~ aq.
NaHC03, brine, dried over MgS04, filtered and concentrated in vacuo to provide a viscous oil. Chromatography of the residue on Si02 (elution with 30 to 60~ acetone:hexanes) provided 238 mg (67~) of compound 5 as a viscous oil.
1H NMR (500 MHz, CDCL3) a 8.44-8.40 (m, 4H), 7.35 (m. 2H), 7.22-7.18 (m, 2H), 6.43 (br s, 2H), 4.98 (m, 1H), 4.74 (m, 1H) ( 3.84 (s, 9H1 , 3.42 (br s, 1H) ( 3. 18 (s, 3H) , 2.92 (m, 1H), 2.6S-2.56 (m, 5H), 2.06-1.98 (m, 1H), 1.70-153 (m, 15H).
Example 6 (S)-1-((3-Trifluoromethylphenyl)-methyl-carbamoyl)-piperi dine-2-carboxylic acid 4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)-butyl ester (6):
Compound 6 was prepared according to the protocol of Example 5, except that N-methyl-3,4,5-trimethoxyaniline was replaced with N-methyl-3-trifluoro-methylaniline.
1NMR (500 MHz, CDC13) 8 8.42-8.39 (m, 4H) , 7.50-6. 16 (m, 10H), 4.99 (m, 1H), 4.64 (m, 1H), 3.29 (m, 1H), 3.20 (s, 3H), 2.93 (m, 1H), 2.67-2.53 (m, 4H), 2.03-1.99 (m, 1H), 1.69-1.53 (m, 13H).
Example 7 (S)-1-((4-Tert-butylphenyl)-methyl-carbamoyl)-piperidine-2-carboxylic acid 4-pyridin-3-yl-1-(3-pyridin-3-yl--propyl)-butyl ester (7):
Compound 7 was prepared according to the protocol of Example 5, except that N-methyl-3,4,5-trimethoxyaniline was replaced with N-methyl-4-tert-butylaniline.
1NMR (500 MHz, CDC13) 8 8.40 (m, 4H), 7.49-7.42 (m, 2H), 7.30 (d, 2H), 7.17 (m. 2H), 7.05 (d, 2H), 4.99 (m, 1H), 4. 64 (m, 1H) , 3. 35 (m, 1H) , 3.14 (s, 3H) , 2 . 84 (dt, 1H) , 2.64-2.52 m, 4H), 2.00-1.95 (m, 1H), 1.70-1.48 (m, 11H), 1.27 (s, 9H) , 1.20-1 .02 (m, 2H) .
Example 8 (S)-1-((4-Isopropylphenyl)-methyl-carbamoyl)-piperidine-2 -carboxylic acid 4-pyridin-3-yl-1-(3-pyridin--3-yl-propyl)-butyl ester (8):
Compound 8 was prepared according to the protocol of Example 5, except that N-WO 98l20893 PCT/US97/20868 --methyl-3,4,5-trimethoxyaniline was replaced with N-methyl-4-iso-propylaniline.
1H NMR (500 MHz, CDC13) a 8.42-8.39 (m, 4H), 7.99-7.43 (m, 2H), 7.18 (m, 2H), 7.14 (d. 2H), 7.06 (d, 2H), 4.99 (m, 1H) , 4 . 64 (m, 1H) , 3. 35 (br d, 1H) , 3. 15 (s, 3H) , 2 . 85 (m, 2H), 2.59 (m, 9H), 1.97 (m, 1H), 1.70-l.99 (m, 11H), l.21 (d, 6H), 1.20-1.02 (m, 2H).
l0 Example 9 (S)-1-{Piperidine-1-carbonyl)-piperidine-2-carboxylic acid 4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)-butyl ester (9) Compound 9 was prepared according to the protocol of Example 5, except that N-methyl-3,4,5-trimethoxyaniline was replaced with N-piperidine.
1H NMR (50D MHz, CDCls) 8 8.42-8.39 (m, 4H) , 7.50-7. 43 (m, 2H), 7.24-7.16 (m, 2H), 4.98 (m, 1H), 4.67 (t, 1H), 3.32-3.09 {m, 8H), 2.64-2.52 (m, 6H), 2.01-1.96 (m, 1H), 1.80-1.30 (m, 15H).
Example 10 (S)-1-{(3,4,5-Trimethoxyphenyl)-methyl-carbamoyl)-piperid ine-2-carboxylic acid 4-pyridin-1-yl-1-(3-pyridin--1-yl-~ropyl ) -butyl ester ( 10 ) Compound 10 was prepared according to the protocols of Examples 1-5, except that 3-bromopyridine 3o was replaced with 1-bromopyridine.
1H NMR {500 MHz, CDC13) 8 8.50 (t, 2H), 7.56 (dq, 2H), 7.18-7.08 (m, 4H), 6.43 {s, 2H), 4.97 (q, 1H), 4.78 (m, 1H) , 3.83 (s, 9H) , 3.44 (br d, 1H) , 3.19 (s, 3H) ( 2. 89 (dt, iH), 2.82-2.73 (m, 4H), 2.07 (br d, 1H), 1.81-1.52 (m, 12H) .
i Example 11 (S)-Piperidine-1,2-dicarboxyiic acid 1-(3,4,5-trimethoxyphenyl) ester 2-(4-pyridin-3-yl-1--(3-pyridin-3-yl-propyl)-butyl) ester (11):
Compound 11 was prepared according to the protocol of Example 5, except that N-methyl-3,4,5-trimethoxyaniline was replaced with 3,4,5-trimethoxyphenol. Compound 11 was obtained as a to mixture of rotomers:
1H NMR (500 MHz, CDC13) a 8.42-8.35 (m), 7.50-7.32 (m), 7.28-7.18 (m), 6.39 (s), 6.27 (s), 5.34-4.90 (m), 4.19-4.01(m), 3.78 (s), 3.75 (s), 3.22 (br dt), 3.14 (quintet), 3.05-2.90 (m), 2.65-2.53 (m), 2.27-2.21 (m), 15. 2. 02 (s) , 1 . 80-1 .95 (m) .
Example 12 (S)-Piperidine-2-carboxylic acid 2-(1-(2-phenyl--20 ethyl)-3-phenyl-propyl ester (12):
Compound I2 was prepared according to the protocols of Examples 3-4, except that compound 2 in Example 3 was replaced with 1,5-diphenylpentan-3-ol.
25 Example 13 (S)-1-((3,4,5-Trimethoxyphenyl)-methyl-carbamoyl)-piperid ine-2-carboxylic acid 1-(2-phenyl-ethyl)-3-phenyl-propyl ester (13):
30 Compound 13 was prepared according to the protocol of Example 5, except that compound 4 was replaced with compound _12.
1H NMR (500 MHz, CDC13) a 7.27 (m, 4H) , 7.20-7.14 (m, 6H) , 6.47 (s, 2H), 5.01 (m, 1H), 4.87 (m, 1H), 3.84 (s, 6H), 35 3. 83 (s, 3H) , 3. 48 (br d, 1H) , 3.23 (s, 3H) , 2 . 94 (dt, 1H), 2.72-2.94 (m, 4H), 2.17-2.10 (m, 1H), 2.00-1.85 (m, CA 02270985 1999-OS-04 .
4H), 1.67-1.60 (m, 2H), 1.45-1.40 (m, 1H), I.30-Z.18 (m, 2H) .
Example 14 4-(Methyl-(2-(1-phenethyl-3-phenyl-propoxycarbonyl)-piper idine-1-carbonyl)-amino)-benzenesulfonic acid (14):
Compound 14 was prepared according to the protocol of Example 13, except that N-methyl-3,4,5-trimethoxyaniline to was replaced with N-methyl-9-aminophenyl sulfonic acid.
Example 15 (S)-Piperidine-2-carboxylic acid 1-benzvloxvmethvl-2--benzyloxyethyl ester (15):
Compound 15 was prepared according to the protocols of Examples 3-4, except that compound 2 in Example 3 was replaced with 1,3-dibenzyloxypropan-2-ol.
Example 16 (S)-1-(Methyl-(9-morpholin-1-yl phenyl)-carbamoyl)-piperi dine-2-carbox~rlic acid 2-benzyloxy-1-(benzyloxy--methyl)-ethyl ester (16):
Compound 16 was prepared according to the protocol of Example 5, except that compound 4 was replaced with compound 15 and N-methyl-3,4,5-trimethoxy-aniline with N-methyl-4-morpholinoaniline.
1H NMR (500 MHz, CDC13) 8 7.34-7.11 (m, 10H), 7.09 (d, 2H) , 6. 84 (d, 2H) , 5.29 (quintet, 1H) , 4 . 81 (br t, IH) , 4. 54 (d, 2H) , 4.99 (dd, 2H) , 3.84 (t, 2H) , 3. 67 (t, 2H) , 3.40 (br d, 1H), 3.15 (s, 3H), 3.09 (t, 4H), 2.86 (dt, 1H), 2.08-2.05 (m, 1H), 1.60-1.44 (m, 2H), 1.27-1.08 (m, 3H) .
i WO 98l20893 PCTlUS97I20868 -Example 17 (S)-1-(Methyl-(4-piperidin-1-yi-phenyl)-carbamoyl)-piperi dine-2-carboxylic acid 2-benzyloxy-1-(benzyloxy --methyl)-ethyl ester (17):
Compound 17 was prepared according to the protocol of Example 16, except that N-methyl-3,4,5-trimethoxyaniline was replaced with N-methyl-4-piperdinoaniline.
'H NMR (500 MHz, CDC13) E 7.36-7.25 (m, 10H) ( 7.06 (d, 2H), 6.86 (d, 2H), 5.29 (quintet, 1H), 4.79 (m, 1H), 4 . 55-4 . 48 (m, 4H) , 3. 66 (m, 4H) , 3.41 (br d, 1H) , 3. 14 (s, 3H), 3.10 (m, 4H), 2.87 (dt, 1H), 2.05 (br d, 1H), 1.73-1.67 (m, 4H), 1.61-1.45 (m, 4H), 1.25-1.08 (m, 3H).
Example 18 (S)-Piperidine-1,2-dicarboxylic acid 2-(2-benzyloxy-1-(benzyloxymethyl)-ethyl)ester 1-quinolin-5-yl ester (I8):
Compound 18 was prepared according to the protocol of Example 16, except that N-methyl-3,4,5--trimethoxyaniline was replaced with 5-hydroxyquinoline.
Compound _18 was a mixture of rotomers.
'H NMR (500 MHz, CDC13) 8 8.89 (dd) , 8.86 (dd) , 8. 90 (d) , 8.24 (d), 7.89 (t), 7.67 (t), 7.63 (t), 7.36-7.18 (m), 5. 44 (quintet) , 5.36 (quintet) , 5.20 (d) , 5. 02 (d) , 4.56-4.94 (m), 4.34 (br d), 4.14 (br d), 3.72-3.56 (m), 3.39 (dt), 3.09 (dt), 2.38 (br t), 1.90-i.49 (m), 1.40-1.29 (m).
Example 19 (S)-Piperidine-1,2-dicarboxylic acid 2-(2-benzyloxy 1-(benzyloxymethyl)-ethyl)ester 1-pyridin-3-yl ester (I9) .........._ .".."..~.-..»~.-.....---,.~T.....~........ ... ........._ -"........".... ....
Compound 19 was prepared according to the protocol of Example 16, except that N-methyl-3,4,5-trimethoxyaniline was replaced with 3-hydroxypyridine. Compound 19 was a mixture of rotomers.
1H NMR (500 MHz, CDC13) a 8.46-8.41 (m), 7.48 (dt), 7.43 (dt) , 7 . 34-7.24 (m) , 7 . 18 (dd) , 5. 40-5. 33 (m) , 5. 03 (dd) 4.57-9.47 (m), 4.17 (br d), 3.69-3.66 (m), 3.27 (dt), 3.05 (dt), 2.33 (br d), 1.81-1.71(m), 1.&9-1.64 (m), l0 1 . 56-1 . 43 (m) , 1 . 35-1 .27 (m) .
Example 20 2-(1,3-Dimethyl-3(3,4,5-trimethoxyphenyl)ureido)-3 phenyl-propanoic acid 4-pyridin-3-yl-1-(3-pyridin--3-yl-propyl)-butyl ester(20):
Compound 20 is prepared according to the protocols of Examples 3-5, by replacing (S)-piperidine-1,2- -dicarboxylic acid 1-tert-butyl ester 2o with N-(tert-butoxycarbonyl)-L-phenylalanine.
Example 21 2-(1,3-Dimethyl-3-(3,4,5-trimethoxyphenyl)ureido)-3-(phen yl)-pro~anoic acid 3-pyridin-3-yl-1-(2-pyridin-3-yl-ethyl)-propyl ester (21l:
Compound 21 is prepared according to the protocols of Examples 3-5, by replacing (S)-piperidine--1,2-dicarboxylic acid 1-tert-butyl ester with 3o N-(tert-butoxycarbonyl)-L-phenylalanine and 1,7-dipyridin-3-yl-heptan-9-oI with 1,5-dipyridin --3-yl-pentan-3-ol.
WO 98I20893 PCTIUS971208b8 -Example 22 N-Methyl-2-phenylethylamine-1,2-dicarboxvlic acid 1-(3,4,5-trimethoxyphenyl) ester 2-(4-pyridin-3-yl -I-(3-pyridin-3-yl-propyl)butyl) ester (22):
Compound 22 is prepared according to the protocol of Example 20, by replacing N-methyl-3,4,5-trimethoxyaniline with 3,4,5-trimethoxyphenol.
Example 23 N-Methyl-2-phenylethylamine-1,2-dicarboxylic acid 1-(3,4,5-trimethoxyphenyl) ester 2-(3-pyridin-3-yl--1-(2-pyridin-3-yl-ethyl)propyl) ester (23):
Compound 23 is prepared according to the protocol of Example 21, by replacing N-methyl-3,4,5-trimethoxyaniline with 3,4,5-trimethoxy-phenol.
Example 24 In order to directly determine the neurotrophic activity of compounds described in this invention, the neurite outgrowth assay was carried out with pheochromocytoma PC12 cells as described by Lyons et al . ( 1994 ) .
PC12 cells are mainatined at 37 degree and 5~
C02 in Dulbecco's modified Eagle's medium (DMEM) suppplemented with 10~ heat-inactivated horse serum, 5$
heat-inactivated fetal bovine serum (FBS), and 1~
3o glutamate. The cells are then plated at 105 per well in 96 well plates coated with 5 ~/cm2 rat tail collagen and allowed to attach overnight. The medium is then replced with DMEM, 2$ heat-inactivated horse serum, 1~
WO 98l20893 PCTIUS97120868 -glutamate, 1-5 ng/ml of NGF (Sigma) and varying concentrations of compound (0.1 nM- 10 nM). The background control culture is administered with 105 ng/ml of NGF alone without compound. Positive control cultures are administered with high concentration of NGF (50 nglml ) .
The compounds described in this invention herein cause a significant increase in neurite outgrowth over background control cultures.
to While we have hereinbefore presented a number of embodiments of this invention, it is apparent that my basic construction can be altered to provide other embodiments which utilize the methods of this invention.
Therefore, it will be appreciated that the scope of this invention is to be defined by the claims appended hereto rather than the specific embodiments which have been presented hereinbefore by way of example.
Claims (23)
1. A pharmaceutically acceptable composition comprising:
a) a neurotrophic amount of a compound having the formula (I):
and pharmaceutically acceptable derivatives thereof, wherein:
A is CH2, oxygen, or NR1;
wherein R1, B and D are independently:
hydrogen, Ar, (C1-C6) straight or branched alkyl, (C2-C6) straight or branched alkenyl or alkynyl, (C5-C7) cycloalkyl substituted (C1-C6) straight or branched alkyl, (C5-C7) cycloalkyl substituted (C3-C6) straight or branched alkenyl or alkynyl, (C5-C7) cycloalkenyl substituted (C1-C6) straight or branched alkyl, (C5-C7) cycloalkenyl substituted (C3-C6) straight or branched alkenyl or alkynyl, Ar-substituted (C1-C6) straight or branched alkyl, or Ar-substituted (C3-C6) straight or branched alkenyl or alkynyl;
wherein any one of the CH2 groups of said alkyl chain in R1, B and D is optionally replaced by O, S, SO, SO2 or NR;
wherein R is hydrogen, (C1-C4) straight or branched alkyl, (C3-C4) straight or branched alkenyl or alkynyl, or (C1-C4) bridging-alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl chain to form a ring, and wherein said ring is optionally fused to Ar;
J is selected from hydrogen, (C1-C6)-straight or branched alkyl, (C3-C6)-straight or branched alkenyl, or -CH2Ar;
K is selected from (C1-C4)-straight or branched alkyl, -CH2Ar, or cyclohexylmethyl; or J and K are taken together with the nitrogen and carbon atoms to which they are respectively bound to form a 5-7 membered heterocyclic ring which may contain a heteroatom selected from O, S, SO and SO2;
Z is O or S;
Y is O or N; wherein when Y is O, then R1 is a lone pair and R2 is selected from Ar, (C1-C6)-straight or branched alkyl, and (C3-C6)-straight or branched alkenyl or alkynyl; and when Y is N, then R1 and R2 are independently selected from the group consisting of Ar, (C1-C6)-straight or branched alkyl, and (C3-C6)-straight or branched alkenyl or alkynyl; or R1 and R2 are taken together to form a heterocyclic 5-6 membered ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine;
wherein Ar is a carboxylic aromatic group selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isotriazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl, benzo[b]
thiophenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, 1,2,3,4-tetrahydro-quinolinyl, isoquinolinyl, 1,2,3,9-tetrahydro-isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, or phenoxazinyl:
wherein Ar is optionally substituted with one to three substituents which are independently selected from hydrogen, halogen, hydroxyl, nitro, -SO3H, trifluoromethyl, trifluoromethoxy, (C1-C6)-straight or branched alkyl, (C2-C6)-straight or branched alkenyl, O-[(C1-C6)-straight or branched alkyl], O-[(C3-C4)-straight or branched alkenyl], O-benzyl, O-phenyl, 1,2-methylenedioxy, -NR3R4, carboxyl, N- (C1-C5-straight or branched alkyl or C3-C5-straight or branched alkenyl) carboxamides, N,N-di-(C1-C5-straight or branched alkyl or C3-C5-straight or branched alkenyl) carboxamides, morpholinyl, piperidinyl, O-Z, CH2- (CH2) q-Z, O-(CH2) q-Z, (CH2)q-Z-O-Z, or CH=CH-Z;
wherein R3 and R4 are independently selected from (C1-C6)-straight or branched alkyl, (C3-C6) straight or branched alkenyl or alkynyl, hydrogen or benzyl; or wherein R3 and R4 are taken together to form a 5-6 membered heterocyclic ring;
wherein Z is selected from 4-methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazyl, quinolyl, 3,5-dimethylisoxazoyl, isoxazoyl, 2-methylthiazoyl, thiazoyl, 2-thienyl, 3-thienyl, or pyrimidyl;
wherein q is 0-2; and n is 0 or 1;
b) a neurotropic factor; and c) a pharmaceutically suitable carrier.
a) a neurotrophic amount of a compound having the formula (I):
and pharmaceutically acceptable derivatives thereof, wherein:
A is CH2, oxygen, or NR1;
wherein R1, B and D are independently:
hydrogen, Ar, (C1-C6) straight or branched alkyl, (C2-C6) straight or branched alkenyl or alkynyl, (C5-C7) cycloalkyl substituted (C1-C6) straight or branched alkyl, (C5-C7) cycloalkyl substituted (C3-C6) straight or branched alkenyl or alkynyl, (C5-C7) cycloalkenyl substituted (C1-C6) straight or branched alkyl, (C5-C7) cycloalkenyl substituted (C3-C6) straight or branched alkenyl or alkynyl, Ar-substituted (C1-C6) straight or branched alkyl, or Ar-substituted (C3-C6) straight or branched alkenyl or alkynyl;
wherein any one of the CH2 groups of said alkyl chain in R1, B and D is optionally replaced by O, S, SO, SO2 or NR;
wherein R is hydrogen, (C1-C4) straight or branched alkyl, (C3-C4) straight or branched alkenyl or alkynyl, or (C1-C4) bridging-alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl chain to form a ring, and wherein said ring is optionally fused to Ar;
J is selected from hydrogen, (C1-C6)-straight or branched alkyl, (C3-C6)-straight or branched alkenyl, or -CH2Ar;
K is selected from (C1-C4)-straight or branched alkyl, -CH2Ar, or cyclohexylmethyl; or J and K are taken together with the nitrogen and carbon atoms to which they are respectively bound to form a 5-7 membered heterocyclic ring which may contain a heteroatom selected from O, S, SO and SO2;
Z is O or S;
Y is O or N; wherein when Y is O, then R1 is a lone pair and R2 is selected from Ar, (C1-C6)-straight or branched alkyl, and (C3-C6)-straight or branched alkenyl or alkynyl; and when Y is N, then R1 and R2 are independently selected from the group consisting of Ar, (C1-C6)-straight or branched alkyl, and (C3-C6)-straight or branched alkenyl or alkynyl; or R1 and R2 are taken together to form a heterocyclic 5-6 membered ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine;
wherein Ar is a carboxylic aromatic group selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isotriazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl, benzo[b]
thiophenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, 1,2,3,4-tetrahydro-quinolinyl, isoquinolinyl, 1,2,3,9-tetrahydro-isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, or phenoxazinyl:
wherein Ar is optionally substituted with one to three substituents which are independently selected from hydrogen, halogen, hydroxyl, nitro, -SO3H, trifluoromethyl, trifluoromethoxy, (C1-C6)-straight or branched alkyl, (C2-C6)-straight or branched alkenyl, O-[(C1-C6)-straight or branched alkyl], O-[(C3-C4)-straight or branched alkenyl], O-benzyl, O-phenyl, 1,2-methylenedioxy, -NR3R4, carboxyl, N- (C1-C5-straight or branched alkyl or C3-C5-straight or branched alkenyl) carboxamides, N,N-di-(C1-C5-straight or branched alkyl or C3-C5-straight or branched alkenyl) carboxamides, morpholinyl, piperidinyl, O-Z, CH2- (CH2) q-Z, O-(CH2) q-Z, (CH2)q-Z-O-Z, or CH=CH-Z;
wherein R3 and R4 are independently selected from (C1-C6)-straight or branched alkyl, (C3-C6) straight or branched alkenyl or alkynyl, hydrogen or benzyl; or wherein R3 and R4 are taken together to form a 5-6 membered heterocyclic ring;
wherein Z is selected from 4-methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazyl, quinolyl, 3,5-dimethylisoxazoyl, isoxazoyl, 2-methylthiazoyl, thiazoyl, 2-thienyl, 3-thienyl, or pyrimidyl;
wherein q is 0-2; and n is 0 or 1;
b) a neurotropic factor; and c) a pharmaceutically suitable carrier.
2. The pharmaceutically acceptable composition according to claim 1, wherein, in compound of formula (I), at least one of B or D is independently represented by the formula - (CH2) r-(X) - (CH2) s-Ar, wherein r is 1-4;
s is 0-1: and each X is independently selected from CH2, O, S, SO, SO2, and NR, wherein R is selected from hydrogen, (C1-C4)-straight or branched alkyl, (C3-C4)-straight or branched alkenyl or alkynyl, or (C1-C4) bridging alkyl wherein a bridge is formed between the nitrogen atom and the Ar group.
s is 0-1: and each X is independently selected from CH2, O, S, SO, SO2, and NR, wherein R is selected from hydrogen, (C1-C4)-straight or branched alkyl, (C3-C4)-straight or branched alkenyl or alkynyl, or (C1-C4) bridging alkyl wherein a bridge is formed between the nitrogen atom and the Ar group.
3. The pharmaceutically acceptable composition according to claim 1, wherein said compound has formula (II) or formula (III):
Formula (II) Formula (III) wherein:
Y, R1, R2, and Ar are as defined in claim 1, and w is 1 or 2.
Formula (II) Formula (III) wherein:
Y, R1, R2, and Ar are as defined in claim 1, and w is 1 or 2.
4. The pharmaceutically acceptable composition according to claim 1, wherein said compound has formula (IV) or formula (V):
Formula (IV) Formula (V) wherein:
Y, R1, R2, and Ar are as defined in claim 1, and w is 1 or 2.
Formula (IV) Formula (V) wherein:
Y, R1, R2, and Ar are as defined in claim 1, and w is 1 or 2.
5. The pharmaceutically acceptable composition according to any one of claims 1-4, wherein Ar is selected from phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, and 1,2,3,4-tetrahydroquinolinyl, and wherein Ar optionally contains one to three substituents which are independently selected from hydrogen, hydroxyl, nitro, trifluoromethyl, (C1-C6)-straight or branched alkyl, O-[(C1-C6)-straight or branched alkyl], halogen, SO3H, or NR3R4.
6. The pharmaceutically acceptable composition according to claim 1, wherein said compound is selected from the group consisting of:
(S)-1-((3,4,5-Trimethoxyphenyl)-methyl-carbamoyl)-piperidine-2-carboxylic acid 4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)-butyl ester;
(S)-1-((3-Trifluoromethylphenyl)-methyl-carbamoyl)-piperidine-2-carboxylic acid 4-pyridin-3-yl-1-(3-pyridin--3-yl-propyl)-butyl ester;
(S)-1-((4-Tert-butylphenyl)-methyl-carbamoyl)-piperidine-2-carboxylic acid 4-pyridin-3-yl-1-(3-pyridin--3-yl-propyl)-butyl ester;
(S)-1-((9-Isopropylphenyl)-methyl-carbamoyl)-piperid in-2-carboxylic acid 4-pyridin-3-yl-1-(3-pyridin--3-yl-propyl)-butyl ester;
(S)-1-(Piperidine-1-carbonyl)-piperidine-2-carboxyli c acid 4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)-butyl ester:
(S)-1-((3,4,5-Trimethoxyphenyl)-methyl-carbamoyl)-piperidine-2-carboxylic acid 4-pyridin-1-yl-1-(3-pyridin--1-yl-propyl)-butyl ester:
(S)-Piperidine-1,2-dicarboxylic acid 1-(3,4,5-trimethoxyphenyl)ester-2-(4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)-butyl)ester;
(S)-1-((3,4,5-Trimethoxyphenyl)-methyl-carbamoyl)-pi peridine-2-carboxylic acid 1-(2-phenyl-ethyl)-3-phenyl--propyl ester;
(S)-Piperidine-2-carboxylic acid 2-1-(2-phenyl- -ethyl)-3-phenyl-propyl ester;
4-(Methyl-(2-(1-phenethyl-3-phenyl-propoxycarbonyl)-piperidine-1-carbonyl)-amino)-benzenesulfonic acid;
(S)-Piperidine-2-carboxylic acid 1-benzyloxy-methyl--2-benzyloxyethyl ester;
(S)-1-(Methyl-(4-morpholin-1-yl-phenyl)-carbamoyl)-piperidine-2-carboxylic acid 2-benzyloxy-1-(benzyloxy--methyl)-ethyl ester;
(S)-1-(Methyl-(4-piperidin-1-yl-phenyl)-carbamoyl)-piperidine-2-carboxylic acid 2-benzyloxy-1-(benzyloxy--methyl)-ethyl ester;
(S)-Piperidine-1,2-dicarboxylic acid 2-(2-benzyloxy--1-(benzyloxymethyl)-ethyl)ester-1-quinolin-5-yl ester;
(S)-Piperidine-1,2-dicarboxylic acid 2-(2-benzyloxy -1-(benzyloxymethyl)-ethyl)ester-1-pyridin-3-yl ester;
2-(1,3-Dimethyl-3(3,4,5-trimethoxyphenyl)ureido)-3 phenyl-propanoic acid 4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)-butyl ester;
2-(1,3-Dimethyl-3-(3,4,5-trimethoxyphenyl)ureido)-3-(phenyl)-propanoic acid 3-pyridin-3-yl-1-(2-pyridin--3-yl-ethyl)-propyl ester N-Methyl-2-phenylethylamine-1,2-dicarboxylic acid 1-(3,4,5-trimethoxyphenyl)ester;
2-(4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)butyl) ester;
N-Methyl-2-phenylethylamine-1,2-dicarboxylic acid 1-(3,4,5-trimethoxyphenyl)ester; or 2-(3-pyridin-3-yl-1-(2-pyridin-3-yl-ethyl)propyl) ester;
and pharmaceutically acceptable derivatives thereof.
(S)-1-((3,4,5-Trimethoxyphenyl)-methyl-carbamoyl)-piperidine-2-carboxylic acid 4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)-butyl ester;
(S)-1-((3-Trifluoromethylphenyl)-methyl-carbamoyl)-piperidine-2-carboxylic acid 4-pyridin-3-yl-1-(3-pyridin--3-yl-propyl)-butyl ester;
(S)-1-((4-Tert-butylphenyl)-methyl-carbamoyl)-piperidine-2-carboxylic acid 4-pyridin-3-yl-1-(3-pyridin--3-yl-propyl)-butyl ester;
(S)-1-((9-Isopropylphenyl)-methyl-carbamoyl)-piperid in-2-carboxylic acid 4-pyridin-3-yl-1-(3-pyridin--3-yl-propyl)-butyl ester;
(S)-1-(Piperidine-1-carbonyl)-piperidine-2-carboxyli c acid 4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)-butyl ester:
(S)-1-((3,4,5-Trimethoxyphenyl)-methyl-carbamoyl)-piperidine-2-carboxylic acid 4-pyridin-1-yl-1-(3-pyridin--1-yl-propyl)-butyl ester:
(S)-Piperidine-1,2-dicarboxylic acid 1-(3,4,5-trimethoxyphenyl)ester-2-(4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)-butyl)ester;
(S)-1-((3,4,5-Trimethoxyphenyl)-methyl-carbamoyl)-pi peridine-2-carboxylic acid 1-(2-phenyl-ethyl)-3-phenyl--propyl ester;
(S)-Piperidine-2-carboxylic acid 2-1-(2-phenyl- -ethyl)-3-phenyl-propyl ester;
4-(Methyl-(2-(1-phenethyl-3-phenyl-propoxycarbonyl)-piperidine-1-carbonyl)-amino)-benzenesulfonic acid;
(S)-Piperidine-2-carboxylic acid 1-benzyloxy-methyl--2-benzyloxyethyl ester;
(S)-1-(Methyl-(4-morpholin-1-yl-phenyl)-carbamoyl)-piperidine-2-carboxylic acid 2-benzyloxy-1-(benzyloxy--methyl)-ethyl ester;
(S)-1-(Methyl-(4-piperidin-1-yl-phenyl)-carbamoyl)-piperidine-2-carboxylic acid 2-benzyloxy-1-(benzyloxy--methyl)-ethyl ester;
(S)-Piperidine-1,2-dicarboxylic acid 2-(2-benzyloxy--1-(benzyloxymethyl)-ethyl)ester-1-quinolin-5-yl ester;
(S)-Piperidine-1,2-dicarboxylic acid 2-(2-benzyloxy -1-(benzyloxymethyl)-ethyl)ester-1-pyridin-3-yl ester;
2-(1,3-Dimethyl-3(3,4,5-trimethoxyphenyl)ureido)-3 phenyl-propanoic acid 4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)-butyl ester;
2-(1,3-Dimethyl-3-(3,4,5-trimethoxyphenyl)ureido)-3-(phenyl)-propanoic acid 3-pyridin-3-yl-1-(2-pyridin--3-yl-ethyl)-propyl ester N-Methyl-2-phenylethylamine-1,2-dicarboxylic acid 1-(3,4,5-trimethoxyphenyl)ester;
2-(4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)butyl) ester;
N-Methyl-2-phenylethylamine-1,2-dicarboxylic acid 1-(3,4,5-trimethoxyphenyl)ester; or 2-(3-pyridin-3-yl-1-(2-pyridin-3-yl-ethyl)propyl) ester;
and pharmaceutically acceptable derivatives thereof.
7. The pharmaceutically acceptable composition according to claim 1, wherein said neurotrophic factor is selected from nerve growth factor (NGF), insulin growth factor (IGF) and active truncated derivatives thereof, acidic fibroblast growth factor (aFGF), basic fibroblast growth factor (bFGF), platelet-derived growth factors (PDGF), brain-derived neurotrophic factor (BDNF), ciliary neurotropic factors (CNTF), glial cell-derived neurotropic factor (GDNF), neurotrophin-3 (NT-3) or neurotrophin 4/5 (NT-4/5).
8. The pharmaceutically acceptable composition according to claim 8, wherein said neurotrophic factor is nerve growth factor (NGF).
9. A method for stimulating neurite growth in a patient or in an ex vivo nerve cell comprising the step of administering to said patient or said nerve a neurotrophic amount of a compound having the formula (I):
Formula (I) and pharmaceutically acceptable derivatives thereof, wherein:
R1, R2, B, D, J, K, A, Y, Z, and n are defined as in claim 1.
Formula (I) and pharmaceutically acceptable derivatives thereof, wherein:
R1, R2, B, D, J, K, A, Y, Z, and n are defined as in claim 1.
10. The method according to claim 9, wherein, in compound of formula (I), at least one of B or D is independently represented by the formula -(CH2)r-(X)-(CH2)s-Ar, wherein r, s, and X are as defined in claim 2.
11. The method according to claim 9, wherein said compound has formula (II) or formula (III):
wherein R1, R2, Y, and Ar are as defined in claim 1, and w is 1 or 2.
wherein R1, R2, Y, and Ar are as defined in claim 1, and w is 1 or 2.
12. The method according to claim 9, wherein said compound has formula (IV) or formula (V):
Formula (IV) Formula (V) wherein R1, R2, Y, and Ar are as defined in claim 1, and w is 1 or 2.
Formula (IV) Formula (V) wherein R1, R2, Y, and Ar are as defined in claim 1, and w is 1 or 2.
13. The method according to any one of claims 9-13, wherein Ar is selected from phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, or 1,2,3,4-tetrahydro- quinolinyl, wherein Ar optionally contains one to three substituents which are independently selected from hydrogen, hydroxyl, nitro, trifluoromethyl, (C1-C6)-straight or branched alkyl, O-[(C1-C6)-straight or branched alkyl], halogen, SO3H, and NR3R4.
14. The method according to claim 9, wherein said compound is selected from:
(S)-1-((3,4,5-Trimethoxyphenyl)-methyl-carbamoyl)-piperidine-2-carboxylic acid 4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)-butyl ester (S)-1-((3-Trifluoromethylphenyl)-methyl-carbamoyl)-piperidine-2-carboxylic acid 4-pyridin-3-yl-1-(3-pyridin--3-yl-propyl)-butyl ester;
(S)-1-((4-Tert-butylphenyl)-methyl-carbamoyl)-piperidine-2-carboxylic acid 4-pyridin-3-yl-1-(3-pyridin--3-yl-propyl)-butyl ester;
(S)-1-((4-Isopropylphenyl)-methyl-carbamoyl)-piperid in-2-carboxylic acid 4-pyridin-3-yl-1-(3-pyridin--3-yl-propyl)-butyl ester;
(S)-1-(Piperidine-1-carbonyl)-piperidine-2-carboxylic acid 4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)-butyl ester;
(S)-1-((3,4,5-Trimethoxyphenyl)-methyl-carbamoyl)-piperidine-2-carboxylic acid 4-pyridin-1-yl-1-(3-pyridin--1-yl-propyl)-butyl ester;
(S)-Piperidine-1,2-dicarboxylic acid 1-(3,4,5-trimethoxyphenyl)ester-2-(4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)-butyl)ester;
(S)-1-((3,4,5-Trimethoxyphenyl)-methyl-carbamoyl)-pi peridine-2-carboxylic acid 1-(2-phenyl-ethyl)-3-phenyl--propyl ester;
(S)-Piperidine-2-carboxylic acid 2-1-(2-phenyl- -ethyl)-3-phenyl-propyl ester;
4-(Methyl-(2-(1-phenethyl-3-phenyl-propoxycarbonyl)-piperidine-1-carbonyl)-amino)-benzenesulfonic acid;
(S)-Piperidine-2-carboxylic acid 1-benzyloxy-methyl--2-benzyloxyethyl ester;
(S)-1-(Methyl-(4-morpholin-1-yl-phenyl)-carbamoyl)-piperidine-2-carboxylic acid 2-benzyloxy-1-(benzyloxy--methyl)-ethyl ester;
(S)-1-(Methyl-(4-piperidin-1-yl-phenyl)-carbamoyl)-piperidine-2-carboxylic acid 2-benzyloxy-1-(benzyloxy--methyl)-ethyl ester;
(S)-Piperidine-1,2-dicarboxylic acid 2-(2-benzyloxy--1-(benzyloxymethyl)-ethyl)ester-1-quinolin-5-yl ester;
(S)-Piperidine-1,2-dicarboxylic acid 2-(2-benzyloxy -1-(benzyloxymethyl)-ethyl)ester-1-pyridin-3-yl ester;
2-(1,3-Dimethyl-3(3,4,5-trimethoxyphenyl)ureido)-3 phenyl-propanoic acid 4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)-butyl ester;
2-(1,3-Dimethyl-3-(3,4,5-trimethoxyphenyl)ureido)-3-(phenyl)-propanoic acid 3-pyridin-3-yl-1-(2-pyridin--3-yl-ethyl)-propyl ester;
N-Methyl-2-phenylethylamine-1,2-dicarboxylic acid 1-(3,4,5-trimethoxyphenyl)ester;
2-(4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)butyl) ester;
N-Methyl-2-phenylethylamine-1,2-dicarboxylic acid 1-(3,4,5-trimethoxyphenyl)ester; or 2-(3-pyridin-3-yl-1-(2-pyridin-3-yl-ethyl)propyl) ester; and pharmaceutically acceptable derivatives thereof.
(S)-1-((3,4,5-Trimethoxyphenyl)-methyl-carbamoyl)-piperidine-2-carboxylic acid 4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)-butyl ester (S)-1-((3-Trifluoromethylphenyl)-methyl-carbamoyl)-piperidine-2-carboxylic acid 4-pyridin-3-yl-1-(3-pyridin--3-yl-propyl)-butyl ester;
(S)-1-((4-Tert-butylphenyl)-methyl-carbamoyl)-piperidine-2-carboxylic acid 4-pyridin-3-yl-1-(3-pyridin--3-yl-propyl)-butyl ester;
(S)-1-((4-Isopropylphenyl)-methyl-carbamoyl)-piperid in-2-carboxylic acid 4-pyridin-3-yl-1-(3-pyridin--3-yl-propyl)-butyl ester;
(S)-1-(Piperidine-1-carbonyl)-piperidine-2-carboxylic acid 4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)-butyl ester;
(S)-1-((3,4,5-Trimethoxyphenyl)-methyl-carbamoyl)-piperidine-2-carboxylic acid 4-pyridin-1-yl-1-(3-pyridin--1-yl-propyl)-butyl ester;
(S)-Piperidine-1,2-dicarboxylic acid 1-(3,4,5-trimethoxyphenyl)ester-2-(4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)-butyl)ester;
(S)-1-((3,4,5-Trimethoxyphenyl)-methyl-carbamoyl)-pi peridine-2-carboxylic acid 1-(2-phenyl-ethyl)-3-phenyl--propyl ester;
(S)-Piperidine-2-carboxylic acid 2-1-(2-phenyl- -ethyl)-3-phenyl-propyl ester;
4-(Methyl-(2-(1-phenethyl-3-phenyl-propoxycarbonyl)-piperidine-1-carbonyl)-amino)-benzenesulfonic acid;
(S)-Piperidine-2-carboxylic acid 1-benzyloxy-methyl--2-benzyloxyethyl ester;
(S)-1-(Methyl-(4-morpholin-1-yl-phenyl)-carbamoyl)-piperidine-2-carboxylic acid 2-benzyloxy-1-(benzyloxy--methyl)-ethyl ester;
(S)-1-(Methyl-(4-piperidin-1-yl-phenyl)-carbamoyl)-piperidine-2-carboxylic acid 2-benzyloxy-1-(benzyloxy--methyl)-ethyl ester;
(S)-Piperidine-1,2-dicarboxylic acid 2-(2-benzyloxy--1-(benzyloxymethyl)-ethyl)ester-1-quinolin-5-yl ester;
(S)-Piperidine-1,2-dicarboxylic acid 2-(2-benzyloxy -1-(benzyloxymethyl)-ethyl)ester-1-pyridin-3-yl ester;
2-(1,3-Dimethyl-3(3,4,5-trimethoxyphenyl)ureido)-3 phenyl-propanoic acid 4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)-butyl ester;
2-(1,3-Dimethyl-3-(3,4,5-trimethoxyphenyl)ureido)-3-(phenyl)-propanoic acid 3-pyridin-3-yl-1-(2-pyridin--3-yl-ethyl)-propyl ester;
N-Methyl-2-phenylethylamine-1,2-dicarboxylic acid 1-(3,4,5-trimethoxyphenyl)ester;
2-(4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)butyl) ester;
N-Methyl-2-phenylethylamine-1,2-dicarboxylic acid 1-(3,4,5-trimethoxyphenyl)ester; or 2-(3-pyridin-3-yl-1-(2-pyridin-3-yl-ethyl)propyl) ester; and pharmaceutically acceptable derivatives thereof.
15. The method according to claim 9, wherein said method is used to treat a patient suffering from Alzheimer's disease, Parkinson's disease, ALS, multiple sclerosis, stroke and ischemia associated with stroke, neural paropathy, other neural degenerative diseases, motor neuron diseases, sciatic crush, peripheral neuropathy, diabetic neuropathy, spinal cord injury or facial nerve crush.
16. The method according to claim 15, omprising the additional step of administering to said patient a neurotrophic factor either as part of a multiple dosage form with said compound or as a separate dosage form.
17. The method according to claim 16, wherein said neurotrophic factor is selected from nerve growth factor (NGF), insulin growth factor (IGF) and active truncated derivatives thereof, acidic fibroblast growth factor (aFGF), basic fibroblast growth factor (bFGF), platelet-derived growth factors (PDGF), brain-derived eurotrophic factor (BDNF), ciliary neurotropic factors CNTF), glial cell-derived neurotropic factor (GDNF), neurotrophin-3 (NT-3) or neurotrophin 4/5 (NT-4/5).
18. The method according to claim 17, wherein said neurotrophic factor is nerve growth factor (NGF).
19. The method according to any one of claims 15-18, wherein said pateint is suffering from diabetes associated peripheral neuropathy.
20. The method according to claim 9, wherein said method is used to stimulate ex vivo nerve regeneration.
21. The method according to claim 20, comprising the additional step of contacting said nerve cell with a neurotrophic factor.
22. The method according to claim 21, wherein said neurotrophic factor is selected from nerve growth factor (NGF), insulin growth factor (IGF) and active truncated derivatives thereof, acidic fibroblast growth factor (a FGF), basic fibroblast growth factor (bFGF), platelet-derived growth factors (PDGF), brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factors (CNTF), glial cell-derived neurotropic factor (GDNF), neurotrophin-3 (NT-3) or neurotrophin 4/5 (NT-4/5).
23.~The method according to claim 22, wherein said neurotrophic factor is nerve growth factor (NGF).
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/749,114 US5780484A (en) | 1996-11-13 | 1996-11-13 | Methods for stimulating neurite growth with piperidine compounds |
| US08/749,114 | 1996-11-13 | ||
| PCT/US1997/020868 WO1998020893A1 (en) | 1996-11-13 | 1997-11-13 | Methods and compositions for stimulating neurite growth using compounds with affinity for fkbp12 in combination with neurotrophic factors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2270985A1 true CA2270985A1 (en) | 1998-05-22 |
Family
ID=25012320
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002270985A Abandoned CA2270985A1 (en) | 1996-11-13 | 1997-11-13 | Methods and compositions for stimulating neurite growth using compounds with affinity for fkbp12 in combination with neurotrophic factors |
Country Status (19)
| Country | Link |
|---|---|
| US (1) | US5780484A (en) |
| EP (2) | EP1666053A1 (en) |
| JP (1) | JP2001503778A (en) |
| KR (1) | KR100537866B1 (en) |
| CN (1) | CN1168443C (en) |
| AR (1) | AR015105A1 (en) |
| AU (1) | AU741186B2 (en) |
| BR (1) | BR9713037A (en) |
| CA (1) | CA2270985A1 (en) |
| CO (1) | CO5080733A1 (en) |
| EA (1) | EA003530B1 (en) |
| IL (1) | IL129557A0 (en) |
| IN (1) | IN183409B (en) |
| NZ (1) | NZ335396A (en) |
| PL (1) | PL191249B1 (en) |
| TW (1) | TW509572B (en) |
| UA (1) | UA61090C2 (en) |
| WO (1) | WO1998020893A1 (en) |
| ZA (1) | ZA9710248B (en) |
Families Citing this family (40)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6133456A (en) * | 1994-08-18 | 2000-10-17 | Ariad Gene Therapeutics, Inc. | Synthetic multimerizing agents |
| US6150527A (en) * | 1994-08-18 | 2000-11-21 | Ariad Pharmaceuticals, Inc. | Synthetic multimerizing agents |
| US20030036654A1 (en) | 1994-08-18 | 2003-02-20 | Holt Dennis A. | Synthetic multimerizing agents |
| US5859031A (en) * | 1995-06-07 | 1999-01-12 | Gpi Nil Holdings, Inc. | Small molecule inhibitors of rotamase enzyme activity |
| ZA98825B (en) * | 1997-02-27 | 1998-10-19 | Guilford Pharm Inc | Method of using neurotrophic carbamates and ureas |
| US6242468B1 (en) * | 1997-02-27 | 2001-06-05 | Jia-He Li | Carbamate and urea compositions and neurotrophic uses |
| US6514686B2 (en) | 1997-04-28 | 2003-02-04 | The University Of British Columbia | Method and composition for modulating amyloidosis |
| US5945441A (en) | 1997-06-04 | 1999-08-31 | Gpi Nil Holdings, Inc. | Pyrrolidine carboxylate hair revitalizing agents |
| US6852496B1 (en) * | 1997-08-12 | 2005-02-08 | Oregon Health And Science University | Methods of screening for agents that promote nerve cell growth |
| US5968921A (en) * | 1997-10-24 | 1999-10-19 | Orgegon Health Sciences University | Compositions and methods for promoting nerve regeneration |
| EA200001247A1 (en) | 1998-06-03 | 2001-08-27 | Джи Пи Ай Нил Холдингс, Инк. | N-BONDED SULPHONAMIDES OF N-HETEROCYCLIC CARBONIC ACIDS OR ISATERES OF CARBONIC ACIDS |
| CN1299346A (en) * | 1998-06-03 | 2001-06-13 | Gpi;Nil控股公司 | Ureas and carbamates of N-heterocyclic carboxylic acids and carboxylic acid isosteres |
| US6331537B1 (en) | 1998-06-03 | 2001-12-18 | Gpi Nil Holdings, Inc. | Carboxylic acids and carboxylic acid isosteres of N-heterocyclic compounds |
| DK1098897T3 (en) | 1998-07-17 | 2004-10-18 | Agouron Pharma | Compounds, Preparations, and Methods for Stimulating Neuronal Growth and Extension |
| GB9815880D0 (en) | 1998-07-21 | 1998-09-16 | Pfizer Ltd | Heterocycles |
| US6395758B1 (en) | 1998-08-14 | 2002-05-28 | Gpi Nil Holdings, Inc. | Small molecule carbamates or ureas for vision and memory disorders |
| US7338976B1 (en) * | 1998-08-14 | 2008-03-04 | Gpi Nil Holdings, Inc. | Heterocyclic esters or amides for vision and memory disorders |
| US6376517B1 (en) * | 1998-08-14 | 2002-04-23 | Gpi Nil Holdings, Inc. | Pipecolic acid derivatives for vision and memory disorders |
| US6462072B1 (en) | 1998-09-21 | 2002-10-08 | Gpi Nil Holdings, Inc. | Cyclic ester or amide derivatives |
| US6228872B1 (en) | 1998-11-12 | 2001-05-08 | Bristol-Myers Squibb Company | Neurotrophic diamide and carbamate agents |
| WO2001002368A1 (en) * | 1999-07-06 | 2001-01-11 | Vertex Pharmaceuticals Incorporated | N-heterocyclic derivatives with neuronal activity |
| US6734211B1 (en) | 1999-07-09 | 2004-05-11 | Oregon Health & Sciences University | Compositions and methods for promoting nerve regeneration |
| US6809107B1 (en) * | 1999-07-09 | 2004-10-26 | Ortho-Mcneil Pharmaceutical, Inc. | Neurotrophic pyrrolidines and piperidines, and related compositions and methods |
| AU7353300A (en) * | 1999-09-08 | 2001-04-10 | Guilford Pharmaceuticals Inc. | Non-peptidic cyclophilin binding compounds and their use |
| EP1227859B1 (en) * | 1999-11-12 | 2006-08-09 | Alcon, Inc | Neurophilin ligands for treating ocular conditions |
| US6417189B1 (en) | 1999-11-12 | 2002-07-09 | Gpi Nil Holdings, Inc. | AZA compounds, pharmaceutical compositions and methods of use |
| US7253169B2 (en) | 1999-11-12 | 2007-08-07 | Gliamed, Inc. | Aza compounds, pharmaceutical compositions and methods of use |
| US6818643B1 (en) | 1999-12-08 | 2004-11-16 | Bristol-Myers Squibb Company | Neurotrophic bicyclic diamides |
| CA2393466C (en) | 1999-12-21 | 2010-01-19 | Gpi Nil Holdings, Inc. | Hydantoin derivative compounds, pharmaceutical compositions, and methods of using same |
| MXPA03006666A (en) | 2001-01-25 | 2004-05-31 | Guilford Pharm Inc | Trisubstituted carbocyclic cyclophilin binding compounds and their use. |
| JP2005500270A (en) * | 2001-05-29 | 2005-01-06 | ギルフォード ファーマシュウティカルズ インコーポレイテッド | Method for treating nerve injury that has occurred as a result of surgery |
| US20040147433A1 (en) * | 2001-06-14 | 2004-07-29 | Marcus Keep | Neuroimmunophilins for selective neuronal radioprotection |
| US6635892B2 (en) * | 2002-01-24 | 2003-10-21 | Pei Electronics, Inc. | Compact integrated infrared scene projector |
| EP1546103B1 (en) * | 2002-10-03 | 2009-03-18 | Vertex Pharmaceuticals Incorporated | Piperazine and piperidine derivatives for treatment of neurological diseases |
| US20060189551A1 (en) * | 2004-10-04 | 2006-08-24 | Duke University | Combination therapies for fungal pathogens |
| CA2590254A1 (en) * | 2004-12-20 | 2006-06-29 | Wyeth | Rapamycin derivatives and the uses thereof in the treatment of neurological disorders |
| GT200500368A (en) * | 2004-12-20 | 2006-07-13 | RAPAMYCIN ANALOGS AND USES OF THE SAME IN THE TREATMENT OF NEUROLOGICAL, PROLIFERATIVE AND INFLAMMATORY DISORDERS | |
| ES2433290T3 (en) * | 2005-02-17 | 2013-12-10 | Astellas Pharma Inc. | Piperazine derivatives for the treatment of urinary incontinence and pain |
| US7935342B2 (en) * | 2006-02-02 | 2011-05-03 | Rinat Neuroscience Corp. | Methods for treating obesity by administering a trkB antagonist |
| NL2000464C2 (en) * | 2006-02-02 | 2007-09-11 | Rinat Neuroscience Corp | Methods for treating unwanted weight loss or eating disorders by administering a TRKB agonist. |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5744485A (en) * | 1994-03-25 | 1998-04-28 | Vertex Pharmaceuticals Incorporated | Carbamates and ureas as modifiers of multi-drug resistance |
| IL115685A (en) * | 1994-11-16 | 2000-08-31 | Vertex Pharma | Amino acid derivatives pharmaceutical compositions containing the same and processes for the preparation thereof |
| US5543423A (en) * | 1994-11-16 | 1996-08-06 | Vertex Pharmaceuticals, Incorporated | Amino acid derivatives with improved multi-drug resistance activity |
| US5614547A (en) * | 1995-06-07 | 1997-03-25 | Guilford Pharmaceuticals Inc. | Small molecule inhibitors of rotamase enzyme |
| US5859031A (en) * | 1995-06-07 | 1999-01-12 | Gpi Nil Holdings, Inc. | Small molecule inhibitors of rotamase enzyme activity |
| US5696135A (en) * | 1995-06-07 | 1997-12-09 | Gpi Nil Holdings, Inc. | Inhibitors of rotamase enzyme activity effective at stimulating neuronal growth |
| US6037370A (en) * | 1995-06-08 | 2000-03-14 | Vertex Pharmaceuticals Incorporated | Methods and compositions for stimulating neurite growth |
| US5801197A (en) * | 1995-10-31 | 1998-09-01 | Gpi Nil Holdings, Inc. | Rotamase enzyme activity inhibitors |
| WO2014051091A1 (en) * | 2012-09-28 | 2014-04-03 | Dic株式会社 | α-ALUMINA MICROPARTICLES AND METHOD FOR PRODUCING SAME |
-
1996
- 1996-11-13 US US08/749,114 patent/US5780484A/en not_active Expired - Lifetime
-
1997
- 1997-11-13 CA CA002270985A patent/CA2270985A1/en not_active Abandoned
- 1997-11-13 IL IL12955797A patent/IL129557A0/en not_active IP Right Cessation
- 1997-11-13 CN CNB971802483A patent/CN1168443C/en not_active Expired - Fee Related
- 1997-11-13 TW TW086116912A patent/TW509572B/en not_active IP Right Cessation
- 1997-11-13 AR ARP970105320A patent/AR015105A1/en not_active Application Discontinuation
- 1997-11-13 CO CO97066753A patent/CO5080733A1/en unknown
- 1997-11-13 NZ NZ335396A patent/NZ335396A/en unknown
- 1997-11-13 UA UA99063269A patent/UA61090C2/en unknown
- 1997-11-13 KR KR10-1999-7004194A patent/KR100537866B1/en not_active IP Right Cessation
- 1997-11-13 WO PCT/US1997/020868 patent/WO1998020893A1/en not_active Application Discontinuation
- 1997-11-13 IN IN2147CA1997 patent/IN183409B/en unknown
- 1997-11-13 BR BR9713037-0A patent/BR9713037A/en not_active Application Discontinuation
- 1997-11-13 ZA ZA9710248A patent/ZA9710248B/en unknown
- 1997-11-13 EA EA199900463A patent/EA003530B1/en not_active IP Right Cessation
- 1997-11-13 PL PL333286A patent/PL191249B1/en not_active IP Right Cessation
- 1997-11-13 EP EP06000328A patent/EP1666053A1/en not_active Ceased
- 1997-11-13 JP JP52286798A patent/JP2001503778A/en active Pending
- 1997-11-13 EP EP97948309A patent/EP0941113A1/en not_active Ceased
- 1997-11-13 AU AU54397/98A patent/AU741186B2/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| WO1998020893A1 (en) | 1998-05-22 |
| CN1168443C (en) | 2004-09-29 |
| PL191249B1 (en) | 2006-04-28 |
| AU5439798A (en) | 1998-06-03 |
| AU741186B2 (en) | 2001-11-22 |
| TW509572B (en) | 2002-11-11 |
| IL129557A0 (en) | 2000-02-29 |
| AR015105A1 (en) | 2001-04-18 |
| EP0941113A1 (en) | 1999-09-15 |
| JP2001503778A (en) | 2001-03-21 |
| PL333286A1 (en) | 1999-11-22 |
| EA199900463A1 (en) | 2000-02-28 |
| UA61090C2 (en) | 2003-11-17 |
| BR9713037A (en) | 2000-04-11 |
| US5780484A (en) | 1998-07-14 |
| ZA9710248B (en) | 1998-05-28 |
| CN1239434A (en) | 1999-12-22 |
| NZ335396A (en) | 2000-11-24 |
| KR20000068964A (en) | 2000-11-25 |
| KR100537866B1 (en) | 2005-12-21 |
| CO5080733A1 (en) | 2001-09-25 |
| EP1666053A1 (en) | 2006-06-07 |
| IN183409B (en) | 1999-12-25 |
| EA003530B1 (en) | 2003-06-26 |
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| EEER | Examination request | ||
| FZDE | Discontinued |